Alkene compounds as farnesoid x receptor modulators

ABSTRACT

The present invention provides compounds of Formula (I): Formula (I) or stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates thereof, wherein all the variables are as defined herein. These compounds modulate the activity of famesoid X receptor (FXR), for example, as agonists. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating a disease, disorder, or condition associated with FXR dysregulation, such as pathological fibrosis, transplant rejection, cancer, osteoporosis, and inflammatory disorders, by using the compounds and pharmaceutical compositions.

CROSS REFERENCE

This application is a 371 application of International Application No.PCT/US2018/058323 filed on Oct. 31, 2018, which claims the benefit ofU.S. Provisional Application Ser. No. 62/580,060, filed Nov. 1, 2017,the content of each is hereby fully incorporated by reference in itsentirety for all purposes.

DESCRIPTION

The present invention relates generally to compounds useful as famesoidX receptor (FXR) modulators, pharmaceutical compositions comprising suchcompounds and to their use in therapy, especially in the treatment orprophylaxis of diseases, disorders, and conditions for which an FXRmodulator is indicated.

FXR or NR1H4 (nuclear receptor subfamily 1, group H, member 4) is anuclear receptor that can activate the expression of specific targetgenes in a ligand-dependent manner. FXR is expressed in the liver,throughout the gastrointestinal tract, colon, ovary, adrenal gland,kidney, and in the gall bladder and biliary tree in humans. FXR forms aheterodimer with Retinoid X Receptor (RXR) and binds to specificresponse elements in target genes to regulate gene transcription (B. M.Forman et al., Cell 1995; 81: 687; W. Seol et al., Mol. Endocrinol.1995; 9: 72). The FXR/RXR heterodimer typically binds to an invertedrepeat of a consensus hexanucleotide sequence (AGGTCA) separated by asingle nucleotide, i.e. an IR-1 sequence. The relevant physiologicalligands of FXR are bile acids including chenodeoxycholic acid and itstaurine-conjugate (D. J. Parks et al., Science 1999; 284: 1365; M.Makishima et al., Science 1999; 284: 1362). FXR activation regulates theexpression of multiple genes that encode enzymes and transportersinvolved in bile acid synthesis, influx, and efflux from the liver andintestine resulting in a net decrease in total endogenous bile acids ina negative feedback loop. FXR is involved in paracrine and endocrinesignaling by upregulating the expression of the cytokine FibroblastGrowth Factor 15 (rodents) or 19 (primates), which can also contributeto the regulation of bile acid concentrations (Holt et al., Genes Dev.2003; 17: 1581; Inagaki et al., Cell Metab 2005; 2: 217). Therefore, FXRis considered to be a master regulator of bile acid homeostasis.

One use of FXR agonists is for the treatment of diseases in which bileacids are dysregulated, including cholestatic diseases (e.g. primarybiliary cirrhosis and primary sclerosing cholangitis) that can lead tofibrosis, cirrhosis, cholangiocarcinoma, hepatocellular carcinoma, liverfailure, and death. While elevated bile acid concentrations in the liverhave deleterious effects, bile acids also affect the microflora andintegrity of the small intestine. Obstruction of bile flow in humans orrodents causes proliferation of intestinal bacteria and mucosal injury,which can lead to bacterial translocation across the mucosal barrier andsystemic infection (Berg, Trends Microbiol. 1995; 3: 149-154). Micelacking FXR have increased ileal levels of bacteria and a compromisedepithelial barrier, while activation of intestinal FXR plays animportant role in preventing bacterial overgrowth and maintaining theintegrity of the intestinal epithelium (Inagaki et al., Proc Natl AcadSci 2006; 103: 3920-3925). Over time, FXR null mice spontaneouslydevelop hepatocellular carcinoma, and this can be abrogated by selectivere-activation of FXR in the intestine (Degirolamo et al., Hepatology 61:161-170). Pharmacological activation of FXR with a small moleculeagonist or transgenic expression of FXR in the intestine can normalizebile acid concentrations, decrease cellular proliferation in hepaticbile ducts, and reduce inflammatory cell infiltration, necrotic area,and liver fibrosis in rodent models of cholestasis (Liu et al., J. Clin.Invest. 2003; 112:1678-1687; Modica et al., Gastroenterology. 2012; 142:355-365). Some of these beneficial effects observed in preclinicalmodels of cholestasis have translated to human patients, and the FXRagonist, obeticholic acid (OCA or OCALIVA™), has been approved for thetreatment of primary biliary cirrhosis(https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm503964.htm).

In addition to controlling bile acid homeostasis, FXR agonists regulatethe hepatic expression of hundreds of genes encoding proteins involvedin cholesterol and lipid metabolism and transport, glucose homeostasis,inflammation, chemotaxis, and apoptosis among other pathways (Zhan etal., PLoS One 2014; 9: e105930; Ijssennagger et al., J Hepatol 2016; 64:1158-1166). Consistent with these broad effects on gene expression, FXRagonists have also been investigated in preclinical models of fibrosis,cancer, inflammatory diseases, and metabolic disorders, includingdyslipidemia, obesity, type 2 diabetes, nonalcoholic fatty liver disease(NAFLD) and metabolic syndrome (Crawley, Expert Opin. Ther. Patents2010; 20:1047-1057).

FXR agonists are also being investigated in human clinical trials forthe treatment of NAFLD, a more advanced form of fatty liver disease,nonalcoholic steatohepatitis (NASH), and associated complications. NAFLDis one of the most common causes of chronic liver disease in the worldtoday (Vernon et al., Aliment Pharmacol Ther 2011; 34:274-285). The riskfactors for developing NAFLD include obesity, type 2 diabetes mellitus(T2DM), insulin resistance, hypertension, and dyslipidemia. In a 6-weekclinical trial in T2DM patients with NAFLD, the FXR agonist OCAstatistically significantly improved insulin sensitivity and reducedbody weight, showing beneficial effects on some of these risk factors(Mudaliar et al., Gastroenterology 2013; 145: 574-582). NASH is the mostsevere and progressive form of NAFLD and includes the histologicalfindings of hepatic steatosis, inflammation, and ballooning degenerationwith varying amounts of pericellular fibrosis (Sanyal et al., Hepatology2015; 61:1392-1405). In a 72-week clinical trial in patients with NASH,OCA statistically significantly improved hepatic steatosis, lobularinflammation, hepatocyte ballooning, and fibrosis as assessed byhistological analyses of liver biopsies (Neuschwander-Tetri et al.,Lancet 2015; 385: 956-965). These data also suggest the potential forFXR agonists to show benefit on clinical outcomes given that NASH is thesecond leading cause of hepatocellular carcinoma (HCC) and livertransplantation in the United States (Wong et al., Hepatology 2014; 59:2188-2195).

The present invention provides novel compounds for treating a disease,disorder, or condition associated with famesoid X receptor (FXR)activity in a patient in need thereof.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides compounds of Formula (I)and (II) as well as the subgenera and species thereof, includingstereoisomers, tautomers, pharmaceutically acceptable salts, andsolvates thereof, which are useful as FXR modulators.

In another aspect, the present invention also provides processes andintermediates for making the compounds of the present invention.

In another aspect, the present invention also provides pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier and atleast one of the compounds of the present invention or stereoisomers,tautomers, pharmaceutically acceptable salts, or solvates thereof.

In another aspect, the compounds of the invention may be used intherapy, either alone or in combination with one or more additionaltherapeutic agents.

The compounds of the invention may be used in the treatment of adisease, disorder, or condition associated with activity of famesoid Xreceptor (FXR) in a patient in need of such treatment by administering atherapeutically effective amount of the compound, or a stereoisomer, atautomer, or a pharmaceutically acceptable salt or solvate thereof, tothe patient. The disease, disorder, or condition may be related topathological fibrosis. The compounds of the invention can be used alone,in combination with one or more compounds of the present invention, orin combination with one or more, e.g., one to two, other therapeuticagents.

The compounds of the invention may be used, either as a single agent orin combination with other agents, in the treatment of a disease,disorder, or condition selected from nonalcoholic steatohepatitis(NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidneydisease, diabetic kidney disease, primary sclerosing cholangitis (PSC),and primary biliary cirrhosis (PBC). The compounds of the invention maybe used, either as a single agent or in combination with other agents,in the treatment of idiopathic pulmonary fibrosis (IPF).

The compounds of the invention may be used for the manufacture of amedicament for the treatment of a disease, disorder, or condition in apatient in need of such treatment.

Other features and advantages of the invention will be apparent from thefollowing detailed description and claims.

DETAILED DESCRIPTION

The present application provides compounds, including all stereoisomers,solvates, prodrugs and pharmaceutically acceptable salt and solvateforms thereof, according to Formula (I). The present application alsoprovides pharmaceutical compositions containing at least one compoundaccording to Formula (I), or a stereoisomer, a tautomer, or apharmaceutically acceptable salt or a solvate thereof, and optionally atleast one additional therapeutic agent. Additionally, the presentapplication provides methods for treating a patient suffering from aFXR-modulated disease or disorder such as for example, biliary fibrosis,liver fibrosis, renal fibrosis, Non-Alcoholic Fatty Liver Disease(NAFLD), Non-Alcoholic Steato-Hepatitis (NASH), primary sclerosingcholangitis (PSC), primary biliary cirrhosis (PBC), and pancreaticfibrosis, by administering to a patient in need of such treatment atherapeutically effective amount of a compound of the present invention,or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt ora solvate thereof, and optionally in combination with at least oneadditional therapeutic agent.

I. Compounds of the Invention

In one embodiment, the present invention provides a compound of Formula(I):

or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt orsolvate thereof; wherein:

X¹ and X⁴ are each independently C or N;

X² and X³ are each independently CR⁵, N, NR⁶, O, or S;

Y is CR⁷, or N;

the dashed straight line is an optional covalent bond;

m and n are each independently an integer of 0, 1, or 2; provided thatwhen m and n are both 0, then the optional covalent bond of the dashedline is absent;

f is an integer of 0, 1, 2, or 3;

Z is 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to10-membered carbocyclyl, or 4- to 10-membered heterocyclyl, wherein thearyl, heteroaryl, carbocyclyl, and heterocyclyl are independentlysubstituted with 0 to 5 R⁸;

L¹ is a covalent bond, O, S, NR¹⁷, —S(O)₂—, C₁₋₃ alkylene, C₁₋₃heteroalkylene, C₂₋₄ alkenylene, C₂₋₄ alkynylene, aryl, or a 5- to6-membered heteroaryl containing 1 to 4 heteroatoms independentlyselected from N, O, and S; wherein the alkylene, heteroalkylene, aryl,and heteroaryl are each independently substituted with 0 to 3 R¹¹;

L² is a covalent bond, O, S, NR¹⁸, C₁₋₃ alkylene, or C₁₋₃heteroalkylene, wherein the alkylene and heteroalkylene areindependently substituted with 0 to 3 R¹⁶;

R^(X) is -L³-R;

L³ is a covalent bond, a C₁₋₃ alkylene, or —C(O)NR¹²—CH₂—, wherein theC₁₋₃ alkylene is substituted with 0 to 3 R¹⁵;

R^(Z) is —CN, —C(O)OR¹³, —C(O)NR^(14a)R^(14b)

R^(e) is C₁₋₆ alkyl, C₃₋₆ cycloalkyl, haloalkyl, hydroxyalkyl,aminoalkyl, alkoxyalkyl, or haloalkoxyalkyl;

each R^(Y) is independently hydrogen, halo, cyano, hydroxyl, amino, C₁₋₆alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl,haloalkoxyalkyl, alkoxy, or haloalkoxy; or alternatively two R^(Y),together with the carbon atoms to which they are attached, form a bridgemoiety; and with the proviso that when Y is N and R^(Y) is attached to acarbon atom adjacent to Y, then R^(Y) is not halo, cyano, hydroxyl,amino, alkoxy, or haloalkoxy;

R¹ is C₁₋₆ alkyl, C₃₋₅ cycloalkyl, or C₄₋₆ heterocyclyl, wherein thealkyl and cycloalkyl are substituted with 0 to 3 R⁹;

R² is 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to10-membered carbocyclyl, or 4- to 10-membered heterocyclyl, wherein thearyl, heteroaryl, carbocyclyl, and heterocyclyl are independentlysubstituted with 0 to 5 R¹⁰;

R³ and R⁴ are each independently hydrogen, C₁₋₆ alkyl, haloalkyl,hydroxyalkyl, aminoalkyl, alkoxyalkyl, or haloalkoxyalkyl;

R⁵ and R⁷ are each independently hydrogen, halo, cyano, hydroxyl, amino,C₁₋₆ alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl,alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy;

R⁶, R¹⁷ and R¹⁸ are each independently is hydrogen, C₁₋₆ alkyl,haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, or haloalkoxyalkyl;

R⁸ and R¹⁰ are each independently halo, cyano, hydroxyl, amino, oxo,—OR^(a), —SR^(a), ═S, —NR^(c)R^(c), ═NH, ═N—OH, ═NR^(a), ═N—OR^(a),—NO₂, —S(O)₂R^(a), —S(O)₂NHR^(b), —S(O)₂NR^(c)R^(c), —S(O)₂OR^(b),—OS(O)₂R^(b), —OS(O)₂OR^(b), —P(O)(OR^(b))(OR^(b)), —C(O)R^(b),—C(NR^(b))R^(b), —C(O)OR^(b), —C(O)NR^(c)R^(c), —C(NR^(b))NR^(c)R^(c),—OC(O)R^(b), —NR^(b)C(O)R^(b), —OC(O)OR^(b), —NR^(b)C(O)OR^(b),—OC(O)NR^(c)R^(c), —NR^(b)C(O)NR^(c)R^(c), —NR^(b)C(NR^(b))R^(b),—NR^(b)C(NR^(b))NR^(c)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl,arylalkyl, heteroaryl, carbocyclyl, or heterocyclyl; wherein the alkyl,aryl, heteroaryl, carbocyclyl, and heterocyclyl, by themselves or aspart of another group, are each independently substituted with 0 to 5R^(d);

R^(b) is each independently hydrogen or R^(a);

R^(c) is each independently R^(b) or alternatively, the two R^(c) aretaken together with the nitrogen atom to which they are bonded form a 4,5, 6 or 7 membered heterocyclyl;

R^(d) is each independently R^(a), alkoxy, haloalkoxy, alkylamino,cycloalkylamino, heterocyclylamino, haloalkyl, hydroxyalkyl, aminoalkyl,cycloalkoxy, heterocyclyloxy, haloalkoxy, alkoxyalkoxy, haloalkylamino,alkoxyalkylamino, haloalkoxyalkylamino, arylamino, aralkylamino,aryloxy, aralkyloxy, heteroaryloxy, heteroarylalkyloxy, alkylthio, halo,cyano, hydroxyl, amino, oxo, —OR^(a), —SR^(a), ═S, —NR^(c)R^(c), ═NH,═N—OH, ═NR^(a), ═N—OR^(a), —NO₂, —S(O)₂R^(a), —S(O)₂NHR^(b),—S(O)₂NR^(c)R^(c), —S(O)₂OR^(b), —OS(O)₂R^(b), —OS(O)₂OR^(b),—P(O)(OR^(b))(OR^(b)), —C(O)R^(b), —C(NR^(b))R^(b), —C(O)OR^(b),—C(O)NR^(c)R^(c), —C(NR^(b))NR^(c)R^(c), —OC(O)R^(b), —NR^(b)C(O)R^(b),—OC(O)OR^(b), —NR^(b)C(O)OR^(b), —NR^(b)C(O)NR^(c)R^(c),—NR^(b)C(NR^(b))R^(b), or —NR^(b)C(NR^(b))NR^(c)R^(c);

R⁹ is each independently halo, cyano, hydroxyl, amino, or C₁₋₆ alkyl;

R¹¹ and R¹⁶ are each independently halo, oxo, cyano, hydroxyl, amino,C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₄₋₆ heterocyclyl, alkylamino, haloalkyl,hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, orhaloalkoxy;

R¹² are each independently hydrogen or C₁₋₄ alkyl;

R¹³ is hydrogen, C₁₋₁₀ alkyl, or glycosyl;

R^(14a) and R^(14b) are each independently hydrogen, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₄₋₆ heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl,aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy; and

R¹⁵ are each independently halo, oxo, cyano, hydroxyl, amino, alkyl,alkoxy, or alkylamino; or alternatively, two R¹⁵, taken together withthe atom(s) to which they are attached, form a carbocyclyl orheterocyclyl moiety.

In any one of the preceding embodiments of Formula (I), X² is N or NR⁶.

It should be understood by one skilled in the art that the dashed circlein Formula (I) denotes an aromatic ring formed by X¹, X², X³, X⁴, andthe carbon atom; and the dashed straight line is an optional covalentbond; and the wavy or squiggly lines indicate the inclusion of geometricisomers, e.g., R³ and R⁴ can be at either cis or trans positions.

In one embodiment of Formula (I), the compound is represented by Formula(Ia):

In one embodiment of Formula (I), the compound is represented by Formula(Ia):

In any one of the preceding embodiments of Formula (I), Formula (Ia), orFormula (Ib), two R^(Y), together form a C₁₋₃ alkylene bridge moiety.(R^(Y))_(f) denotes one or more optional substituent groups on any ofthe ring member atoms, and each of R^(Y) is independent and can be thesame or different.

In any one of the preceding embodiments of Formula (I), Formula (Ia), orFormula (Ib), the

moiety is

In any one of the preceding embodiments of Formula (I), Formula (Ia), orFormula (Ib), the

moiety is

h and g are each independently an integer of 0 or 1;

e is an integer of 1 or 2;

a is an integer of 1 or 2;

b is an integer of 1 or 2;

f is an integer of 0, 1, or 2; and

each R^(Y) is independently hydrogen, halo, cyano, hydroxyl, amino, C₁₋₆alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl,haloalkoxyalkyl, alkoxy, or haloalkoxy.

In any one of the preceding embodiments of Formula (I), Formula (Ia), orFormula (Ib), the

moiety is:

In any one of the preceding embodiments of Formula (I), Formula (Ia), orFormula (Ib), Z is phenyl or 5- to 10-membered heteroaryl, wherein thephenyl and heteroaryl are independently substituted with 0 to 5 R⁸,wherein R⁸ is the same as defined above.

In any one of the preceding embodiments of Formula (I), Formula (Ia), orFormula (Ib), L¹ is a covalent bond.

In any one of the preceding embodiments of Formula (I), Formula (Ia), orFormula (Ib), —Z—R^(x) is selected from

wherein the Z moiety is further substituted with 0 to 3 R⁸, and R⁸ isthe same as defined above.

In any one of the preceding embodiments of Formula (I), Formula (Ia), orFormula (Ib), Y is N.

In any one of the preceding embodiments of Formula (I), Formula (Ia), orFormula (Ib), Y is CH; and L¹ is a covalent bond, O, S, or NH.

In any one of the preceding embodiments of Formula (I), Formula (Ia), orFormula (Ib), R² is phenyl or 6-membered heteroaryl, wherein the phenyland heteroaryl are substituted with 0 to 3 R¹⁰.

In any one of the preceding embodiments of Formula (I), Formula (Ia), orFormula (Ib), L² is a covalent bond.

In any one of the preceding embodiments of Formula (I), Formula (Ia), orFormula (Ib), R³ and R⁴ are each independently hydrogen or C₁₋₆ alkyl.

In one embodiment of Formula (I), the compound is represented by Formula(II):

X¹ is C or N;

X² and X³ are each independently CH, N, O, or S;

Z is phenyl or a 5- to 10-membered heteroaryl, wherein the phenyl andheteroaryl are independently substituted with 0 to 3 R⁸;

m and n are each independently an integer of 0 or 1; provided that whenm and n are both 0, then the optional covalent bond of the dashed lineis absent;

R^(X) is —C(O)OR¹³;

each R^(Y) is independently hydrogen, halo, cyano, hydroxyl, amino, C₁₋₆alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl,haloalkoxyalkyl, alkoxy, or haloalkoxy;

f is an integer of 0, 1, or 2;

R¹ is C₁₋₆ alkyl or C₃₋₅ cycloalkyl, wherein the alkyl and cycloalkylare independently substituted with 0 to 3 R⁹;

R² is phenyl or 6-membered heteroaryl, wherein the phenyl and heteroarylare independently substituted with 0 to 3 R¹⁰; and

R⁸, R⁹, R¹⁰, and R¹³ are the same as defined above.

In one embodiment of Formula (II), the

moiety is or

In any one of the preceding embodiments of Formula (II), R² is phenyl orpyridinyl, each of which is independently substituted with 0 to 3 R¹⁰.

In any one of the preceding embodiments of Formula (II), wherein m and nare both 1.

In any one of the preceding embodiments of Formula (II), f is 0.

In any one of the preceding embodiments of Formula (II), Z is a 5- or6-membered monocyclic heteroaryl or 8- to 10-membered bicyclicheteroaryl, wherein each of the heteroaryls is independently substitutedwith 0 to 3 R⁸.

In any one of the preceding embodiments of Formula (II), R^(X) is—C(O)OH.

In one embodiment of Formula (I), Formula (Ia), Formula (Ib), or Formula(II), X¹ is C.

In one embodiment of Formula (I), Formula (Ia), Formula (Ib), or Formula(II), X² is N.

In one embodiment of Formula (I), Formula (Ia), Formula (Ib), or Formula(II), X³ is O.

In one embodiment of Formula (I), Formula (Ia), or Formula (Ib), X⁴ isC.

In one embodiment of Formula (I), Formula (Ia), or Formula (Ib), X¹ is Cand X⁴ is C.

In one embodiment of Formula (I) Formula (Ia), Formula (Ib), or Formula(II), one of X² and X³ is N and the other of X² and X³ is O.

In one embodiment of Formula (I), Formula (Ia), Formula (Ib), or Formula(II), X² is N and X³ is O.

In one embodiment of Formula (I), Formula (Ia), Formula (Ib), or Formula(II), X² is O and X³ is N.

In one embodiment of Formula (I), Formula (Ia), Formula (Ib), or Formula(II), X¹ is C; X² is N; and X³ is O.

In one embodiment of Formula (I), Formula (Ia), or Formula (Ib), X¹ isC; one of X² and X³ is N and the other of X² and X³ is O; and X⁴ is C.

In one embodiment of Formula (I), Formula (Ia), or Formula (Ib), X¹ isC; X² is N; X³ is O; and X⁴ is C.

In one embodiment of Formula (I), Formula (Ia), or Formula (Ib), X¹ isC; X² is O; X³ is N; and X⁴ is C.

In one embodiment of Formula (I), Formula (Ia), Formula (Ib), or Formula(II), X¹ is N; X² is N; and X³ is N.

In one embodiment of Formula (I), Formula (Ia), or Formula (Ib), the

moiety is

In one embodiment of Formula (II), the

moiety is

In one embodiment of Formula (I), Formula (Ia), Formula (Ib), or Formula(II), the

moiety is:

In one embodiment of Formula (I), Formula (Ia), Formula (Ib), or Formula(II), L¹ is a covalent bond, C₁₋₂ alkylene, C₁₋₂ heteroalkylene, C₂₋₄alkenylene, C₂₋₄ alkynylene, phenyl, or a 5- to 6-membered heteroarylcontaining 1 to 3 heteroatoms independently selected from N, O, and S;wherein the alkylene, phenyl, heteroalkylene, and heteroaryl are eachindependently substituted with 0 to 3 R¹¹.

In one embodiment of Formula (I), Formula (Ia), Formula (Ib), or Formula(II), L¹ is a covalent bond, —CH₂—, —CH₂CH₂—, —CH₂O—, —OCH₂—, —CH═CH—,phenyl, or a 5- to 6-membered heteroaryl containing 1 to 3 heteroatomsindependently selected from N, O, and S; wherein the phenyl andheteroaryl are each independently substituted with 0 to 2 R¹¹.

In one embodiment of Formula (I), Formula (Ia), Formula (Ib), or Formula(II), L¹ is a covalent bond, phenyl, thiazolyl, oxadiazolyl,thiadiazolyl, or pyridinyl.

In one embodiment of Formula (I), Formula (Ia), Formula (Ib), or Formula(II), Z is 6- to 10-membered aryl or 5- to 10-membered heteroaryl,wherein the aryl and heteroaryl are independently substituted with 0 to3 R⁸.

In one embodiment of Formula (I), Formula (Ia), Formula (Ib), or Formula(II), Z is 1,5-naphthyridinyl, benzo[d]imidazolyl, benzo[d]isothiazolyl,benzo[d]oxazolyl, benzo[d]thiazolyl, cinnolinyl,imidazo[3,4-a]pyridinyl, indazolyl, indolyl, isoquinolinyl, phenyl,pyrazinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[4,3-b]pyridinyl,pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolo[2,1-f]triazinyl,pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-d] pyrimidinyl,pyrrolo[3,2-b]pyridinyl, quinolinonyl, quinolinyl, quinoxalinyl,thiazolo[5,4-b] pyridinyl, or thiazolyl, each independently substitutedwith 0 to 2 R⁸.

In one embodiment of Formula (I), Formula (Ia), Formula (Ib), or Formula(II), L¹ is a covalent bond, phenyl, thiazolyl, oxadiazolyl,thiadiazolyl, or pyridinyl; and Z is 6- to 10-membered aryl or 5- to10-membered heteroaryl, wherein the aryl and heteroaryl areindependently substituted with 0 to 3 R⁸.

In one embodiment of Formula (I), Formula (Ia), Formula (Ib), or Formula(II), L¹ is a covalent bond, phenyl, thiazolyl, oxadiazolyl,thiadiazolyl, or pyridinyl; and Z is 1,5-naphthyridinyl,benzo[d]imidazolyl, benzo[d]isothiazolyl, benzo[d]oxazolyl,benzo[d]thiazolyl, cinnolinyl, imidazo[3,4-a]pyridinyl, indazolyl,indolyl, isoquinolinyl, phenyl, pyrazinyl, pyrazolo[1,5-a]pyridinyl,pyrazolo[4,3-b]pyridinyl, pyrazolyl, pyridazinyl, pyridinyl,pyrimidinyl, pyrrolo[2,1-f]triazinyl, pyrrolo[2,3-b]pyridinyl,pyrrolo[2,3-d] pyrimidinyl, pyrrolo[3,2-b]pyridinyl, quinolinonyl,quinolinyl, quinoxalinyl, thiazolo[5,4-b] pyridinyl, or thiazolyl, eachindependently substituted with 0 to 2 R⁸.

In one embodiment of Formula (I), Formula (Ia), Formula (Ib), or Formula(II), R^(X) is -L³-R;

-   L³ is a covalent bond or C₁₋₂ alkylene; wherein the C₁₋₂ alkylene is    substituted with 0 to 2 R¹⁵;-   R^(Z) is —CN, —C(O)OR¹³, —C(O)NR^(14a)R^(14b),

and

-   R¹⁵ are each independently F, C₁, or —CH₃; or alternatively, two    R¹⁵, taken together with the atom(s) to which they are attached,    form C₃₋₆ cycloalkyl.

In one embodiment of Formula (I) or Formula (II),

-   R^(X) is -L³-R^(Z);-   L³ is a covalent bond or C₁₋₂ alkylene; wherein the C₁₋₂ alkylene is    substituted with 0 to 2 R¹⁵;-   R^(Z) is —CN, —C(O)OH, —C(O)NH₂,

and

-   R¹⁵ are each independently F, C₁, or —CH₃; or alternatively, two    R¹⁵, taken together with the atom(s) to which they are attached,    form cyclopropyl.

In one embodiment of Formula (I), Formula (Ia), Formula (Ib), or Formula(II), R^(X) is —CN, —C(O)OH, —CH₂C(O)OH, —C(O)NH₂, —C(O)NHS(O)₂CH₃

In one embodiment of Formula (I), Formula (Ia), Formula (Ib), or Formula(II), R¹ is C₁₋₆ alkyl or C₃₋₅ cycloalkyl, wherein the alkyl andcycloalkyl are independently substituted with 0 to 3 R⁹.

In one embodiment of Formula (I), Formula (Ia), Formula (Ib), or Formula(II), R¹ is C₁₋₃ alkyl or C₃₋₅ cycloalkyl, wherein the alkyl andcycloalkyl are independently substituted with 0 to 3 R⁹.

In one embodiment of Formula (I), Formula (Ia), Formula (Ib), or Formula(II), R¹ is C₃₋₄ cycloalkyl substituted with 0 to 3 R⁹.

In one embodiment of Formula (I), Formula (Ia), Formula (Ib), or Formula(II), R¹ is cyclopropyl.

In one embodiment of Formula (I), Formula (Ia), Formula (Ib), or Formula(II), L² is a covalent bond or C₁₋₂ alkylene, wherein the alkylene isindependently substituted with 0 to 3 R¹⁶.

In one embodiment of Formula (I), Formula (Ia), Formula (Ib), or Formula(II), L² is a covalent bond.

In one embodiment of Formula (I), Formula (Ia), Formula (Ib), or Formula(II), R² is phenyl or pyridinyl, each independently substituted with 1to 2 R¹⁰;

In one embodiment of Formula (I), Formula (Ia), Formula (Ib), or Formula(II), L² is a covalent bond or C₁₋₂ alkylene, wherein the alkylene isindependently substituted with 0 to 3 R¹⁶; and R² is phenyl orpyridinyl, each independently substituted with 1 to 2 R¹⁰.

In one embodiment of Formula (I), Formula (Ia), Formula (Ib), or Formula(II), L² is a covalent bond; and R² is phenyl or pyridinyl, eachindependently substituted with 1 to 2 R¹⁰.

One embodiment provides a compound of Formula (I), Formula (Ia), Formula(Ib), or Formula (II), or a stereoisomer, a tautomer, or apharmaceutically acceptable salt or solvate thereof; wherein:

the

moiety is

the

moiety is:

-   L¹ is a covalent bond, phenyl, thiazolyl, oxadiazolyl, thiadiazolyl,    or pyridinyl;-   Z is 1,5-naphthyridinyl, benzo[d]imidazolyl, benzo[d]isothiazolyl,    benzo[d]oxazolyl, benzo[d]thiazolyl, cinnolinyl,    imidazo[3,4-a]pyridinyl, indazolyl, indolyl, isoquinolinyl, phenyl,    pyrazinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[4,3-b]pyridinyl,    pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl,    pyrrolo[2,1-f]triazinyl, pyrrolo[2,3-b] pyridinyl, pyrrolo[2,3-d]    pyrimidinyl, pyrrolo[3,2-b]pyridinyl, quinolinonyl, quinolinyl,    quinoxalinyl, thiazolo[5,4-b] pyridinyl, or thiazolyl, each    independently substituted with 0 to 2 R⁸;-   R^(X) is —CN, —C(O)OH, —CH₂C(O)OH, —C(O)NH₂, —C(O)NHS(O)₂CH₃,

-   R¹ is cyclopropyl;-   R² is phenyl or pyridinyl, each independently substituted with 1 to    2 R¹⁰;-   R³ is hydrogen;-   R⁴ is hydrogen or —CH₃;-   R⁸ is each independently F, C₁, —CH₃, —CH₂CH₃, —CH₂OCH₃, —CF₃,    —OCH₃, —OCD₃, —OCH₂CH₃, —CH(CH₃)₂, —OCH₂CH₂OCH₃, —OCHF₂, —OCH₂CHF₂,    —CH₂(cyclopropyl), —O(cyclopropyl), —O(cyclobutyl),    —O(difluorocyclobutyl), —O(fluorocyclobutyl), —O(oxetanyl),    —O(tetrahydrofuranyl), or —OCH₂(methoxyphenyl);-   L² is a covalent bond; and-   R¹⁰ is each independently C₁, —CF₃, or —OCF₃.

In one embodiment, the present invention provides, inter alia, compoundsselected from any one of the Examples as described in the specification,or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt orsolvate thereof.

II. Pharmaceutical Compositions, Therapeutic Utilities, and Combinations

In another embodiment, the present invention provides a compositioncomprising at least one of the compounds of the present invention, or astereoisomer, a tautomer, or a pharmaceutically acceptable salt or asolvate thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atleast one of the compounds of the present invention or a stereoisomer, atautomer, or a pharmaceutically acceptable salt or a solvate thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition, comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a stereoisomer, a tautomer, or a pharmaceuticallyacceptable salt or a solvate thereof.

In another embodiment, the present invention provides a process formaking a compound of the present invention.

In another embodiment, the present invention provides an intermediatefor making a compound of the present invention.

In another embodiment, the present invention provides a pharmaceuticalcomposition as defined above further comprising one or more additionaltherapeutic agents.

In another embodiment, the present invention provides a method for thetreatment of a disease, disorder, or condition associated withdysregulation of bile acids in a patient in need of such treatment, andthe method comprises administering a therapeutically effective amount ofa compound of the present invention, or a stereoisomer, a tautomer, or apharmaceutically acceptable salt or solvate thereof, to the patient.

In another embodiment, the present invention provides a method for thetreatment of a disease, disorder, or condition associated with activityof famesoid X receptor (FXR) in a patient in need of such treatmentcomprising administering a therapeutically effective amount of acompound of the present invention, or a stereoisomer, a tautomer, or apharmaceutically acceptable salt or solvate thereof, to the patient.

In another embodiment, the present invention provides a method for thetreatment of the disease, disorder, or condition comprisingadministering to a patient in need of such treatment a therapeuticallyeffective amount of at least one of the compounds of the presentinvention, alone, or, optionally, in combination with another compoundof the present invention and/or at least one other type of therapeuticagent.

In another embodiment, the present invention provides a method foreliciting an famesoid X receptor (FXR) agonizing effect in a patientcomprising administering a therapeutically effective amount of acompound of the present invention, or a stereoisomer, a tautomer, or apharmaceutically acceptable salt or solvate thereof, to the patient.

In some embodiments, the disease, disorder, or condition is associatedwith FXR dysfunction include pathological fibrosis, cancer, inflammatorydisorders, metabolic, or cholestatic disorders.

In some embodiments, the disease, disorder, or condition is associatedwith fibrosis, including liver, biliary, renal, cardiac, dermal, ocular,and pancreatic fibrosis.

In other embodiments, the disease, disorder, or condition is associatedwith cell-proliferative disorders, such as cancer. In some embodiments,the cancer includes solid tumor growth or neoplasia. In otherembodiments, the cancer includes tumor metastasis. In some embodiments,the cancer is of the liver, gall bladder, small intestine, largeintestine, kidney, prostate, bladder, blood, bone, brain, breast,central nervous system, cervix, colon, endometrium, esophagus,genitalia, genitourinary tract, head, larynx, lung, muscle tissue, neck,oral or nasal mucosa, ovary, pancreas, skin, spleen, stomach, testicle,or thyroid. In other embodiments, the cancer is a carcinoma, sarcoma,lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, orseminoma.

Examples of diseases, disorders, or conditions associated with theactivity of FXR that can be prevented, modulated, or treated accordingto the present invention include, but are not limited to, transplantinjection, fibrotic disorders (e. g., liver fibrosis, kidney fibrosis),inflammatory disorders (e.g., acute hepatitis, chronic hepatitis,non-alcoholic steatohepatitis (NASH), irritable bowel syndrome (IBS),inflammatory bowel disease (IBD)), as well as cell-proliferativedisorders (e.g., cancer, myeloma, fibroma, hepatocellular carcinoma,colorectal cancer, prostate cancer, leukemia, Kaposi's sarcoma, solidtumors).

The fibrotic disorders, inflammatory disorders, as well ascell-proliferative disorders that are suitable to be prevented ortreated by the compounds of the present invention include, but are notlimited to, non-alcoholic fatty liver disease (NAFLD), alcoholic ornon-alcoholic steatohepatitis (NASH), acute hepatitis, chronichepatitis, liver cirrhosis, primary biliary cirrhosis, primarysclerosing cholangitis, drug-induced hepatitis, biliary cirrhosis,portal hypertension, regenerative failure, liver hypofunction, hepaticblood flow disorder, nephropathy, irritable bowel syndrome (IBS),inflammatory bowel disease (IBD), abnormal pancreatic secretion, benignprostatic hyperplasia, neuropathic bladder disease, diabeticnephropathy, focal segmental glomerulosclerosis, IgA nephropathy,nephropathy induced by drugs or transplantation, autoimmune nephropathy,lupus nephritis, liver fibrosis, kidney fibrosis, chronic kidney disease(CKD), diabetic kidney disease (DKD), skin fibrosis, keloids, systemicsclerosis, scleroderma, virally-induced fibrosis, idiopathic pulmonaryfibrosis (IPF), interstitial lung disease, non-specific interstitialpneumonia (NSIP), usual interstitial pneumonia (UIP), radiation-inducedfibrosis, familial pulmonary fibrosis, airway fibrosis, chronicobstructive pulmonary disease (COPD), spinal cord tumor, hernia ofintervertebral disk, spinal canal stenosis, heart failure, cardiacfibrosis, vascular fibrosis, perivascular fibrosis, foot-and-mouthdisease, cancer, myeloma, fibroma, hepatocellular carcinoma, colorectalcancer, prostate cancer, leukemia, chronic lymphocytic leukemia,Kaposi's sarcoma, solid tumors, cerebral infarction, cerebralhemorrhage, neuropathic pain, peripheral neuropathy, age-related maculardegeneration (AMD), glaucoma, ocular fibrosis, comeal scarring, diabeticretinopathy, proliferative vitreoretinopathy (PVR), cicatricialpemphigoid glaucoma filtration surgery scarring, Crohn's disease orsystemic lupus erythematosus; keloid formation resulting from abnormalwound healing; fibrosis occurring after organ transplantation,myelofibrosis, and fibroids. In one embodiment, the present inventionprovides a method for the treatment of a fibrotic disorder, aninflammatory disorder, or a cell-proliferative disorder, comprisingadministering to a patient in need of such treatment a therapeuticallyeffective amount of at least one of the compounds of the presentinvention, alone, or, optionally, in combination with another compoundof the present invention and/or at least one other type of therapeuticagent.

In another embodiment, the present invention provides a compound of thepresent invention for use in therapy.

In another embodiment, the present invention provides a compound of thepresent invention for use in therapy for the treatment of a fibroticdisorder, an inflammatory disorder, or a cell-proliferative disorderthereof.

In another embodiment, the present invention also provides the use of acompound of the present invention for the manufacture of a medicamentfor the treatment of a fibrotic disorder, an inflammatory disorder, or acell-proliferative disorder thereof.

In another embodiment, the present invention provides a method for thetreatment of a fibrotic disorder, an inflammatory disorder, or acell-proliferative disorder, comprising administering to a patient inneed thereof a therapeutically effective amount of a first and secondtherapeutic agent, wherein the first therapeutic agent is a compound ofthe present invention.

In another embodiment, the present invention provides a combinedpreparation of a compound of the present invention and additionaltherapeutic agent(s) for simultaneous, separate or sequential use intherapy.

In another embodiment, the present invention provides a combinedpreparation of a compound of the present invention and additionaltherapeutic agent(s) for simultaneous, separate or sequential use in thetreatment of a fibrotic disorder, an inflammatory disorder, or acell-proliferative disorder.

The compounds of the present invention may be employed in combinationwith additional therapeutic agent(s), such as one or more anti-fibroticand/or anti-inflammatory therapeutic agents.

In one embodiment, additional therapeutic agent(s) used in combinedpharmaceutical compositions or combined methods or combined uses, areselected from one or more, preferably one to three, of the followingtherapeutic agents: TGFβ receptor inhibitors (for example,galunisertib), inhibitors of TGFβ synthesis (for example, pirfenidone),inhibitors of vascular endothelial growth factor (VEGF),platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF)receptor kinases (for example, nintedanib), humanized anti-αvβ6 integrinmonoclonal antibody (for example, 3G9), human recombinant pentraxin-2,recombinant human Serum Amyloid P, recombinant human antibody againstTGFβ-1, -2, and -3, endothelin receptor antagonists (for example,macitentan), interferon gamma, c-Jun amino-terminal kinase (JNK)inhibitor (for example, 4-[[9-[(3S)-tetrahydro-3-furanyl]-8-[(2,4,6-trifluorophenyl)amino]-9H-purin-2-yl]amino]-trans-cyclohexanol, 3-pentylbenzeneacetic acid (PBI-4050),tetra-substituted porphyrin derivative containing manganese (III),monoclonal antibody targeting eotaxin-2, interleukin-13 (IL-13) antibody(for example, lebrikizumab, tralokinumab), bispecific antibody targetinginterleukin 4 (IL-4) and interleukin 13 (IL-13), NK1 tachykinin receptoragonist (for example, Sar⁹, Met(O₂)¹¹-Substance P), CintredekinBesudotox, human recombinant DNA-derived, IgG1 kappa monoclonal antibodyto connective growth factor, and fully human IgG1 kappa antibody,selective for CC-chemokine ligand 2 (for example, carlumab, CCX140),antioxidants (for example, N-acetylcysteine), phosphodiesterase 5 (PDE5)inhibitors (for example, sildenafil), agents for treatment ofobstructive airway diseases such as muscarinic antagonists (for example,tiotropium, ipatropium bromide), adrenergic β2 agonists (for example,salbutamol, salmeterol), corticosteroids (for example, triamcinolone,dexamethasone, fluticasone), immunosuppressive agents (for example,tacrolimus, rapamycin, pimecrolimus), and therapeutic agents useful forthe treatment of fibrotic conditions, such as liver, biliary, and kidneyfibrosis, Non-Alcoholic Fatty Liver Disease (NALFD), Non-AlcoholicSteato-Hepatitis (NASH), cardiac fibrosis, Idiopathic Pulmonary Fibrosis(IPF), and systemic sclerosis. The therapeutic agents useful for thetreatment of such fibrotic conditions include, but are not limited to,FXR agonists (for example OCA, GS-9674, and LJN452), LOXL2 inhibitors(for example simtuzumab), LPA1 antagonists (for example, BMS-986020 andSAR 100842), PPAR modulators (for example, elafibrinor, pioglitazone,and saroglitazar, IVA337), SSAO/VAP-1 inhibitors (for example, PXS-4728Aand SZE5302), ASK-1 inhibitors (for example GS-4997 or selonsertib), ACCinhibitors (for example, CP-640186 and NDI-010976 or GS-0976), FGF21mimetics (for example, LY2405319 and BMS-986036), caspase inhibitors(for example, emricasan), NOX4 inhibitors (for example, GKT137831),MGAT2 inhibitor (for example, BMS-963272), αV integrin inhibitors (forexample, abituzumab) and bile acid/fatty acid conjugates (for examplearamchol). The FXR agonists of various embodiments of the presentinvention may also be used in combination with one or more therapeuticagents such as CCR2/5 inhibitors (for example, cenicriviroc), Galectin-3inhibitors (for example, TD-139, GR-MD-02), leukotriene receptorantagonists (for example, tipelukast, montelukast), SGLT2 inhibitors(for example, dapagliflozin, remogliflozin), GLP-1 receptor agonists(for example, liraglutide and semaglutide), FAK inhibitors (for example,GSK-2256098), CB1 inverse agonists (for example, JD-5037), CB2 agonists(for example, APD-371 and JBT-101), autotaxin inhibitors (for example,GLPG1690), prolyl t-RNA synthetase inhibitors (for example,halofugenone), FPR2 agonists (for example, ZK-994), and THR agonists(for example, MGL:3196). In another embodiment, additional therapeuticagent(s) used in combined pharmaceutical compositions or combinedmethods or combined uses, are selected from one or more, preferably oneto three, of immunoncology agents, such as Alemtuzumab, Atezolizumab,Ipilimumab, Nivolumab, Ofatumumab, Pembrolizumab, and Rituximab.

The compounds of this invention can be administered for any of the usesdescribed herein by any suitable means, for example, orally, such astablets, capsules (each of which includes sustained release or timedrelease formulations), pills, powders, granules, elixirs, tinctures,suspensions, syrups, and emulsions; sublingually; bucally; parenterally,such as by subcutaneous, intravenous, intramuscular, or intrastemalinjection, or infusion techniques (e.g., as sterile injectable aqueousor non-aqueous solutions or suspensions); nasally, includingadministration to the nasal membranes, such as by inhalation spray;topically, such as in the form of a cream or ointment; or rectally suchas in the form of suppositories. They can be administered alone, butgenerally will be administered with a pharmaceutical carrier selected onthe basis of the chosen route of administration and standardpharmaceutical practice.

The term “pharmaceutical composition” means a composition comprising acompound of the invention in combination with at least one additionalpharmaceutically acceptable carrier. A “pharmaceutically acceptablecarrier” refers to media generally accepted in the art for the deliveryof biologically active agents to animals, in particular, mammals,including, i.e., adjuvant, excipient or vehicle, such as diluents,preserving agents, fillers, flow regulating agents, disintegratingagents, wetting agents, emulsifying agents, suspending agents,sweetening agents, flavoring agents, perfuming agents, anti-bacterialagents, anti-fungal agents, lubricating agents and dispensing agents,depending on the nature of the mode of administration and dosage forms.Pharmaceutically acceptable carriers are formulated according to anumber of factors well within the purview of those of ordinary skill inthe art. These include, without limitation: the type and nature of theactive agent being formulated; the subject to which the agent-containingcomposition is to be administered; the intended route of administrationof the composition; and the therapeutic indication being targeted.Pharmaceutically acceptable carriers include both aqueous and nonaqueousliquid media, as well as a variety of solid and semi-solid dosage forms.Such carriers can include a number of different ingredients andadditives in addition to the active agent, such additional ingredientsbeing included in the formulation for a variety of reasons, e.g.,stabilization of the active agent, binders, etc., well known to those ofordinary skill in the art. Descriptions of suitable pharmaceuticallyacceptable carriers, and factors involved in their selection, are foundin a variety of readily available sources such as, for example,Remington's Pharmaceutical Sciences, 18th Edition (1990).

The terms “treating” or “treatment” as used herein refer to an approachfor obtaining beneficial or desired results, including clinical results,by using a compound or a composition of the present invention. Forpurposes of this invention, beneficial or desired clinical resultsinclude, but are not limited to, one or more of the following:decreasing the severity and/or frequency one or more symptoms resultingfrom the disease, disorder, or condition; diminishing the extent of orcausing regression of the disease, disorder, or condition; stabilizingthe disease, disorder, or condition (e.g., preventing or delaying theworsening of the disease, disorder, or condition); delay or slowing theprogression of the disease, disorder, or condition; ameliorating thedisease, disorder, or condition state; decreasing the dose of one ormore other medications required to treat the disease, disorder, orcondition; and/or increasing the quality of life.

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.01 to about 5000 mg per day, preferably between about 0.01 toabout 1000 mg per day, and most preferably between about 0.01 to about250 mg per day. Intravenously, the most preferred doses will range fromabout 0.01 to about 10 mg/kg/minute during a constant rate infusion.Compounds of this invention may be administered in a single daily dose,or the total daily dosage may be administered in divided doses of two,three, or four times daily.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, e.g., oral tablets, capsules,elixirs, and syrups, and consistent with conventional pharmaceuticalpractices.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 0.1 milligram to about 2000 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.1-95% by weight based on the total weight of the composition.

A typical capsule for oral administration contains at least one of thecompounds of the present invention (250 mg), lactose (75 mg), andmagnesium stearate (15 mg). The mixture is passed through a 60 meshsieve and packed into a No. 1 gelatin capsule.

A typical injectable preparation is produced by aseptically placing atleast one of the compounds of the present invention (250 mg) into avial, aseptically freeze-drying and sealing. For use, the contents ofthe vial are mixed with 2 mL of physiological saline, to produce aninjectable preparation.

The present invention includes within its scope pharmaceuticalcompositions comprising, as an active ingredient, a therapeuticallyeffective amount of at least one of the compounds of the presentinvention, alone or in combination with a pharmaceutical carrier.Optionally, compounds of the present invention can be used alone, incombination with other compounds of the invention, or in combinationwith one or more, preferably one to three, other therapeutic agent(s),e.g., ASK-1 inhibitors, CCR2/5 antagonists, autotaxin inhibitors, LPA1receptor antagonists or other pharmaceutically active material.

The above other therapeutic agents, when employed in combination withthe compounds of the present invention may be used, for example, inthose amounts indicated in the Physicians'Desk Reference, as in thepatents set out above, or as otherwise determined by one of ordinaryskill in the art.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of the present invention and a secondtherapeutic agent are combined in a single dosage unit they areformulated such that although the active ingredients are combined in asingle dosage unit, the physical contact between the active ingredientsis minimized (that is, reduced). For example, one active ingredient maybe enteric coated. By enteric coating one of the active ingredients, itis possible not only to minimize the contact between the combined activeingredients, but also, it is possible to control the release of one ofthese components in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with amaterial that affects a sustained-release throughout thegastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer, and the other component is also coated with a polymersuch as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

The compounds of the present invention can be administered alone or incombination with one or more, preferably one to three, additionaltherapeutic agents. By “administered in combination” or “combinationtherapy” it is meant that the compound of the present invention and oneor more, preferably one to three, additional therapeutic agents areadministered concurrently to the mammal being treated. When administeredin combination, each component may be administered at the same time orsequentially in any order at different points in time. Thus, eachcomponent may be administered separately but sufficiently closely intime so as to provide the desired therapeutic effect.

The compounds of the present invention are also useful as standard orreference compounds, for example as a quality standard or control, intests or assays involving FXR agonists. Such compounds may be providedin a commercial kit, for example, for use in pharmaceutical researchinvolving FXR agonist activity. For example, a compound of the presentinvention could be used as a reference in an assay to compare its knownactivity to a compound with an unknown activity. This would ensure theexperimenter that the assay was being performed properly and provide abasis for comparison, especially if the test compound was a derivativeof the reference compound. When developing new assays or protocols,compounds according to the present invention could be used to test theireffectiveness.

The present invention also encompasses an article of manufacture. Asused herein, article of manufacture is intended to include, but not belimited to, kits and packages. The article of manufacture of the presentinvention, comprises: (a) a first container; (b) a pharmaceuticalcomposition located within the first container, wherein the composition,comprises: a first therapeutic agent, comprising a compound of thepresent invention or a pharmaceutically acceptable salt form thereof;and, (c) a package insert stating that the pharmaceutical compositioncan be used for the treatment of dyslipidemias and the sequelae thereof.In another embodiment, the package insert states that the pharmaceuticalcomposition can be used in combination (as defined previously) with asecond therapeutic agent for the treatment of fibrosis and the sequelaethereof. The article of manufacture can further comprise: (d) a secondcontainer, wherein components (a) and (b) are located within the secondcontainer and component (c) is located within or outside of the secondcontainer. Located within the first and second containers means that therespective container holds the item within its boundaries.

The first container is a receptacle used to hold a pharmaceuticalcomposition. This container can be for manufacturing, storing, shipping,and/or individual/bulk selling. First container is intended to cover abottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation),or any other container used to manufacture, hold, store, or distribute apharmaceutical product.

The second container is one used to hold the first container and,optionally, the package insert. Examples of the second containerinclude, but are not limited to, boxes (e.g., cardboard or plastic),crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks.The package insert can be physically attached to the outside of thefirst container via tape, glue, staple, or another method of attachment,or it can rest inside the second container without any physical means ofattachment to the first container. Alternatively, the package insert islocated on the outside of the second container. When located on theoutside of the second container, it is preferable that the packageinsert is physically attached via tape, glue, staple, or another methodof attachment. Alternatively, it can be adjacent to or touching theoutside of the second container without being physically attached.

The package insert is a label, tag, marker, etc. that recitesinformation relating to the pharmaceutical composition located withinthe first container. The information recited will usually be determinedby the regulatory agency governing the area in which the article ofmanufacture is to be sold (e.g., the United States Food and DrugAdministration). Preferably, the package insert specifically recites theindications for which the pharmaceutical composition has been approved.The package insert may be made of any material on which a person canread information contained therein or thereon. Preferably, the packageinsert is a printable material (e.g., paper, plastic, cardboard, foil,adhesive-backed paper or plastic, etc.) on which the desired informationhas been formed (e.g., printed or applied).

III. Definitions

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all stereo and optical isomers andracemates thereof where such isomers exist. Unless otherwise indicated,all chiral (enantiomeric and diastereomeric) and racemic forms arewithin the scope of the invention. Many geometric isomers of C═C doublebonds, C═N double bonds, ring systems, and the like can also be presentin the compounds, and all such stable isomers are contemplated in thepresent invention. Cis- and trans- (or E- and Z-) geometric isomers ofthe compounds of the present invention are described and may be isolatedas a mixture of isomers or as separated isomeric forms. The presentcompounds can be isolated in optically active or racemic forms.Optically active forms may be prepared by resolution of racemic forms orby synthesis from optically active starting materials. All processesused to prepare compounds of the present invention and intermediatesmade therein are considered to be part of the present invention. Whenenantiomeric or diastereomeric products are prepared, they may beseparated by conventional methods, for example, by chromatography orfractional crystallization. Depending on the process conditions the endproducts of the present invention are obtained either in free (neutral)or salt form. Both the free form and the salts of these end products arewithin the scope of the invention. If so desired, one form of a compoundmay be converted into another form. A free base or acid may be convertedinto a salt; a salt may be converted into the free compound or anothersalt; a mixture of isomeric compounds of the present invention may beseparated into the individual isomers. Compounds of the presentinvention, free form and salts thereof, may exist in multiple tautomericforms, in which hydrogen atoms are transposed to other parts of themolecules and the chemical bonds between the atoms of the molecules areconsequently rearranged. It should be understood that all tautomericforms, insofar as they may exist, are included within the invention. Asused herein, “a compound of the invention” or “compounds of theinvention” means one or more compounds encompassed by any one of Formula(I), (IIa), and (IIb), or stereoisomers, tautomers, or pharmaceuticallyacceptable salts or solvates thereof.

As used herein, the term “alkyl” or “alkylene” is intended to includeboth branched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. While “alkyl” denotes amonovalent saturated aliphatic radical (such as ethyl), “alkylene”denotes a bivalent saturated aliphatic radical (such as ethylene). Forexample, “C₁ to C₁₀ alkyl” or “C₁₋₁₀ alkyl” is intended to include C₁,C₂, C₃, C₄, C₅, C₆ C₇, C₈, C₉, and C₁₀ alkyl groups. “C₁ to C₁₀alkylene” or “C₁₋₁₀ alkylene”, is intended to include C₁, C₂, C₃, C₄,C₅, C₆, C₇, C₈, C₉, and C₁₀ alkylene groups. Additionally, for example,“C₁ to C₆ alkyl” or “C₁₋₆ alkyl” denotes alkyl having 1 to 6 carbonatoms; and “C₁ to C₆ alkylene” or “C₁₋₆ alkylene” denotes alkylenehaving 1 to 6 carbon atoms. Alkyl group can be unsubstituted orsubstituted with at least one hydrogen being replaced by anotherchemical group. Example alkyl groups include, but are not limited to,methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl(e.g., n-butyl, isobutyl, t-butyl), and pentyl (e.g., n-pentyl,isopentyl, neopentyl). When “C₀ alkyl” or “C₀ alkylene” is used, it isintended to denote a direct bond.

Unless otherwise indicated, the term “lower alkyl” as employed hereinalone or as part of another group includes both straight and branchedchain hydrocarbons containing 1 to 8 carbons, and the terms “alkyl” and“alk” as employed herein alone or as part of another group includes bothstraight and branched chain hydrocarbons containing 1 to 20 carbons,preferably 1 to 10 carbons, more preferably 1 to 8 carbons, in thenormal chain, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl,isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the variousbranched chain isomers thereof, and the like.

“Heteroalkyl” refers to an alkyl group where one or more carbon atomshave been replaced with a heteroatom, such as, O, N, or S. For example,if the carbon atom of the alkyl group which is attached to the parentmolecule is replaced with a heteroatom (e.g., O, N, or S) the resultingheteroalkyl groups are, respectively, an alkoxy group (e.g., —OCH₃,etc.), an alkylamino (e.g., —NHCH₃, —N(CH₃)₂, etc.), or a thioalkylgroup (e.g., —SCH₃). If a non-terminal carbon atom of the alkyl groupwhich is not attached to the parent molecule is replaced with aheteroatom (e.g., O, N, or S) and the resulting heteroalkyl groups are,respectively, an alkyl ether (e.g., —CH₂CH₂—O—CH₃, etc.), analkylaminoalkyl (e.g., —CH₂NHCH₃, —CH₂N(CH₃)₂, etc.), or a thioalkylether (e.g., —CH₂—S—CH₃). If a terminal carbon atom of the alkyl groupis replaced with a heteroatom (e.g., O, N, or S), the resultingheteroalkyl groups are, respectively, a hydroxyalkyl group (e.g.,—CH₂CH₂—OH), an aminoalkyl group (e.g., —CH₂NH₂), or an alkyl thiolgroup (e.g., —CH₂CH₂—SH). A heteroalkyl group can have, for example, 1to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. AC₁-C₆ heteroalkyl group means a heteroalkyl group having 1 to 6 carbonatoms.

“Alkenyl” or “alkenylene” is intended to include hydrocarbon chains ofeither straight or branched configuration having the specified number ofcarbon atoms and one or more, preferably one to two, carbon-carbondouble bonds that may occur in any stable point along the chain. While“alkenyl” denotes a monovalent radical, “alkenylene” denotes a bivalentradical. For example, “C₂ to C₆ alkenyl” or “C₂₋₆ alkenyl” (oralkenylene), is intended to include C₂, C₃, C₄, C₅, and C₆ alkenylgroups. Examples of alkenyl include, but are not limited to, ethenyl,1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3, pentenyl,4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl,2-methyl-2-propenyl, and 4-methyl-3-pentenyl.

“Alkynyl” or “alkynylene” is intended to include hydrocarbon chains ofeither straight or branched configuration having one or more, preferablyone to three, carbon-carbon triple bonds that may occur in any stablepoint along the chain. While “alkynyl” denotes a monovalent radical,“alkynylene” denotes a bivalent radical. For example, “C₂ to C₆ alkynyl”or “C₂₋₆ alkynyl” (or alkynylene), is intended to include C₂, C₃, C₄,C₅, and C₆ alkynyl groups; such as ethynyl, propynyl, butynyl, pentynyl,and hexynyl.

As used herein, “arylalkyl” (a.k.a. aralkyl), “heteroarylalkyl”“carbocyclylalkyl” or “heterocyclylalkyl” refers to an acyclic alkylradical in which one of the hydrogen atoms bonded to a carbon atom,typically a terminal or sp³ carbon atom, is replaced with an aryl,heteroaryl, carbocyclyl, or heterocyclyl radical, respectively. Typicalarylalkyl groups include, but are not limited to, benzyl,2-phenylethan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl,2-naphthophenylethan-1-yl and the like. The arylalkyl, heteroarylalkyl,carbocyclylalkyl, or heterocyclylalkyl group can comprise 4 to 20 carbonatoms and 0 to 5 heteroatoms, e.g., the alkyl moiety may contain 1 to 6carbon atoms.

The term “benzyl”, as used herein, refers to a methyl group on which oneof the hydrogen atoms is replaced by a phenyl group, wherein said phenylgroup may optionally be substituted with 1 to 5 groups, preferably 1 to3 groups, —OH, —OCH₃, C₁, F, Br, I, —CN, —NO₂, —NH₂, —NH(CH₃), —N(CH₃)₂,—CF₃, —OCF₃, —C(═O)CH₃, —SCH₃, —S(═O)CH₃, —S(═O)₂CH₃, —CH₃, —CH₂CH₃,—CO₂H, and —CO₂CH₃. “Benzyl” can also be represented by formula “Bn”.

The term “lower alkoxy”, “alkoxy” or “alkyloxy”, “aryloxy” or “aralkoxy”refers to any of the above alkyl, aralkyl or aryl groups linked to anoxygen atom. “C₁ to C₆ alkoxy” or “C₁₋₆ alkoxy” (or alkyloxy), isintended to include C₁, C₂, C₃, C₄, C₅, and C₆ alkoxy groups. Examplealkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy(e.g., n-propoxy and isopropoxy), and t-butoxy. Similarly, “loweralkylthio”, “alkylthio”, “thioalkoxy”, “arylthio”, or “aralkylthio”represents an alkyl, aryl, or aralkyl group as defined above with theindicated number of carbon atoms attached through a sulfur bridge; forexample methyl-S— and ethyl-S—.

The term “alkanoyl” or “alkylcarbonyl” as used herein alone or as partof another group refers to alkyl linked to a carbonyl group. Forexample, alkylcarbonyl may be represented by alkyl-C(O)—. “C₁ to C₆alkylcarbonyl” (or alkylcarbonyl), is intended to include C₁, C₂, C₃,C₄, C₅, and C₆ alkyl-C(O)— groups.

The term “alkylsulfonyl” or “sulfonamide” as used herein alone or aspart of another group refers to alkyl or amino linked to a sulfonylgroup. For example, alkylsulfonyl may be represented by —S(O)₂R′, whilesulfonamide may be represented by —S(O)₂NR^(c)R^(d). R′ is C₁ to C₆alkyl; and R^(c) and R^(d) are the same as defined below for “amino”.

The term “carbamate” as used herein alone or as part of another grouprefers to oxygen linked to an amido group. For example, carbamate may berepresented by N(R^(c)R^(d))—C(O)—O—, and R^(c) and R^(d) are the sameas defined below for “amino”.

The term “amido” as used herein alone or as part of another group refersto amino linked to a carbonyl group. For example, amido may berepresented by N(R^(c)R^(d))—C(O)—, and R^(c) and R^(d) are the same asdefined below for “amino”.

The term “amino” is defined as —NR^(c1)R^(c2), wherein R^(c1) and R^(c2)are independently H or C₁₋₆ alkyl; or alternatively, R^(c1) and R^(c2),taken together with the atoms to which they are attached, form a 3- to8-membered heterocyclic ring which is optionally substituted with one ormore group selected from halo, cyano, hydroxyl, amino, oxo, C₁₋₆ alkyl,alkoxy, and aminoalkyl. When R^(c1) or R^(c2) (or both of them) is C₁₋₆alkyl, the amino group can also be referred to as alkylamino. Examplesof alkylamino group include, without limitation, —NH₂, methylamino,ethylamino, propylamino, isopropylamino and the like.

The term “aminoalkyl” refers to an alkyl group on which one of thehydrogen atoms is replaced by an amino group. For example, aminoalkylmay be represented by N(R^(c1)R^(c2))-alkylene-. “C₁ to C₆” or “C₁₋₆”aminoalkyl” (or aminoalkyl), is intended to include C₁, C₂, C₃, C₄, C₅,and C₆ aminoalkyl groups.

The term “halogen” or “halo” as used herein alone or as part of anothergroup refers to chlorine, bromine, fluorine, and iodine, with chlorineor fluorine being preferred.

“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with one or more halogens. “C₁ to C₆haloalkyl” or “C₁₋₆ haloalkyl” (or haloalkyl), is intended to includeC₁, C₂, C₃, C₄, C₅, and C₆ haloalkyl groups. Examples of haloalkylinclude, but are not limited to, fluoromethyl, difluoromethyl,trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl,2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examplesof haloalkyl also include “fluoroalkyl” that is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms, substituted with 1 or morefluorine atoms. The term “polyhaloalkyl” as used herein refers to an“alkyl” group as defined above which includes from 2 to 9, preferablyfrom 2 to 5, halo substituents, such as F or C₁, preferably F, such aspolyfluoroalkyl, for example, CF₃CH₂, CF₃ or CF₃CF₂CH₂.

“Haloalkoxy” or “haloalkyloxy” represents a haloalkyl group as definedabove with the indicated number of carbon atoms attached through anoxygen bridge. For example, “C₁ to C₆ haloalkoxy” or “C₁₋₆ haloalkoxy”,is intended to include C₁, C₂, C₃, C₄, C₅, and C₆ haloalkoxy groups.Examples of haloalkoxy include, but are not limited to,trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluorothoxy. Otherexamples of haloalkoxy also include “fluoroalkoxy” which represents afluoroalkyl group as defined above with the indicated number of carbonatoms attached through an oxygen bridge. Similarly, “haloalkylthio” or“thiohaloalkoxy” represents a haloalkyl group as defined above with theindicated number of carbon atoms attached through a sulphur bridge; forexample trifluoromethyl-S—, and pentafluoroethyl-S—. The term“polyhaloalkyloxy” as used herein refers to an “alkoxy” or “alkyloxy”group as defined above which includes from 2 to 9, preferably from 2 to5, halo substituents, such as F or C₁, preferably F, such aspolyfluoroalkoxy, for example, —OCH₂CF₃, —OCF₃, or —OCH₂CF₂CF₃.

“Hydroxyalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with 1 or more hydroxyl (OH). “C₁ to C₆hydroxyalkyl” (or hydroxyalkyl), is intended to include C₁, C₂, C₃, C₄,C₅, and C₆ hydroxyalkyl groups.

The term “cycloalkyl” refers to cyclized alkyl groups, including mono-,bi- or poly-cyclic ring systems. “C₃ to C₇ cycloalkyl” or “C₃₋₇cycloalkyl” is intended to include C₃, C₄, C₅, C₆, and C₇ cycloalkylgroups. Example cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbomyl. Branchedcycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropylare included in the definition of “cycloalkyl”.

The term “cycloheteroalkyl” refers to cyclized heteroalkyl groups,including mono-, bi- or poly-cyclic ring systems. “C₃ to C₇cycloheteroalkyl” or “C₃₋₇ cycloheteroalkyl” is intended to include C₃,C₄, C₅, C₆, and C₇ cycloheteroalkyl groups. Example cycloheteroalkylgroups include, but are not limited to, oxetanyl, tetrahydrofuranyl,tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl,and piperazinyl. Branched cycloheteroalkyl groups, such aspiperidinylmethyl, piperazinylmethyl, morpholinylmethyl,pyridinylmethyl, pyridizylmethyl, pyrimidylmethyl, and pyrazinylmethyl,are included in the definition of “cycloheteroalkyl”.

As used herein, the term “azacyclyl” refers to a cycloheteroalkylcontaining one or more nitrogen atoms in the ring. Example azacyclylgroups include, but are not limited to, pyrrolidinyl, piperidinyl,morpholinyl, and piperazinyl.

As used herein, “carbocycle”, “carbocyclyl”, or “carbocyclic” isintended to mean any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclicor 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered polycyclic(including bicyclic or tricyclic) hydrocarbon ring, any of which may besaturated or partially unsaturated. That is, the term “carbocycle”,“carbocyclyl”, or “carbocyclic” includes, without limitation, cycloalkyland cycloalkenyl. Examples of such carbocycles include, but are notlimited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl,cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl,adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane(decalin), [2.2.2]bicyclooctane, fluorenyl, indanyl, adamantyl, andtetrahydronaphthyl (tetralin). As shown above, bridged rings are alsoincluded in the definition of carbocycle (e.g., [2.2.2]bicyclooctane).Preferred carbocycles, unless otherwise specified, are cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, indanyl, and tetrahydronaphthyl. Abridged ring occurs when one or more, preferably one to three, carbonatoms link two non-adjacent carbon atoms. Preferred bridges are one ortwo carbon atoms. It is noted that a bridge always converts a monocyclicring into a tricyclic ring. When a ring is bridged, the substituentsrecited for the ring may also be present on the bridge.

Furthermore, the term “carbocyclyl”, including “cycloalkyl” and“cycloalkenyl”, as employed herein alone or as part of another groupincludes saturated or partially unsaturated (containing 1 or 2 doublebonds) cyclic hydrocarbon groups containing 1 to 3 rings, includingmonocyclicalkyl, bicyclicalkyl and tricyclicalkyl, containing a total of3 to 20 carbons forming the rings, preferably 3 to 10 carbons or 3 to 6carbons, forming the ring and which may be fused to 1 or 2 aromaticrings as described for aryl, which include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl andcyclododecyl, cyclohexenyl,

any of which groups may be optionally substituted with 1 to 4substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy,arylalkyl, cycloalkyl, alkylamido, alkanoylamino, oxo, acyl,arylcarbonylamino, nitro, cyano, thiol and/or alkylthio and/or any ofthe alkyl substituents.

As used herein, the term “bicyclic carbocycle” or “bicyclic carbocyclicgroup” is intended to mean a stable 9- or 10-membered carbocyclic ringsystem that contains two fused rings and consists of carbon atoms. Ofthe two fused rings, one ring is a benzo ring fused to a second ring;and the second ring is a 5- or 6-membered carbon ring which is saturatedor partially unsaturated. The bicyclic carbocyclic group may be attachedto its pendant group at any carbon atom which results in a stablestructure. The bicyclic carbocyclic group described herein may besubstituted on any carbon if the resulting compound is stable. Examplesof a bicyclic carbocyclic group are, but not limited to,1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and indanyl.

As used herein, the term “aryl”, as employed herein alone or as part ofanother group, refers to monocyclic or polycyclic (including bicyclicand tricyclic) aromatic hydrocarbons, including, for example, phenyl,naphthyl, anthracenyl, and phenanthranyl. Aryl moieties are well knownand described, for example, in Lewis, R. J., ed., Hawley's CondensedChemical Dictionary, 13th Edition, John Wiley & Sons, Inc., New York(1997). In one embodiment, the term “aryl” denotes monocyclic andbicyclic aromatic groups containing 6 to 10 carbons in the ring portion(such as phenyl or naphthyl including 1-naphthyl and 2-naphthyl). Forexample, “C₆ or C₁₀ aryl” or “C₆₋₁₀ aryl” refers to phenyl and naphthyl.Unless otherwise specified, “aryl”, “C₆ or C₁₀ aryl”, “C₆₋₁₀ aryl”, or“aromatic residue” may be unsubstituted or substituted with 1 to 5groups, preferably 1 to 3 groups, selected from —OH, —OCH₃, F, C₁, Br,I, —CN, —NO₂, —NH₂, —NH(CH₃), —N(CH₃)₂, —CF₃, —OCF₃, —C(O)CH₃, —SCH₃,—S(O)CH₃, —S(O)₂CH₃, —CH₃, —CH₂CH₃, —CO₂H, and —CO₂CH₃.

As used herein, the term “heterocycle”, “heterocyclyl”, or “heterocyclicgroup” is intended to mean a stable 3-, 4-, 5-, 6-, or 7-memberedmonocyclic or 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-memberedpolycyclic (including bicyclic and tricyclic) heterocyclic ring that issaturated, or partially unsaturated, and that contains carbon atoms and1, 2, 3 or 4 heteroatoms independently selected from the groupconsisting of N, O and S; and including any polycyclic group in whichany of the above-defined heterocyclic rings is fused to a carbocyclic oran aryl (e.g., benzene) ring. That is, the term “heterocycle”,“heterocyclyl”, or “heterocyclic group” includes non-aromatic ringsystems, such as heterocycloalkyl and heterocycloalkenyl. The nitrogenand sulfur heteroatoms may optionally be oxidized (i.e., N—O andS(O)_(p), wherein p is 0, 1 or 2). The nitrogen atom may be substitutedor unsubstituted (i.e., N or NR wherein R is H or another substituent,if defined). The heterocyclic ring may be attached to its pendant groupat any heteroatom or carbon atom that results in a stable structure. Theheterocyclic rings described herein may be substituted on carbon or on anitrogen atom if the resulting compound is stable. A nitrogen in theheterocycle may optionally be quaternized. It is preferred that when thetotal number of S and O atoms in the heterocycle exceeds 1, then theseheteroatoms are not adjacent to one another. It is preferred that thetotal number of S and O atoms in the heterocycle is not more than 1.Examples of hetercyclyl include, without limitation, azetidinyl,piperazinyl, piperidinyl, piperidonyl, piperonyl, pyranyl, morpholinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,morpholinyl, and dihydrofuro[2,3-b]tetrahydrofuran.

As used herein, the term “bicyclic heterocycle” or “bicyclicheterocyclic group” is intended to mean a stable 9- or 10-memberedheterocyclic ring system which contains two fused rings and consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, O and S. Of the two fused rings, one ring isa 5- or 6-membered monocyclic aromatic ring comprising a 5-memberedheteroaryl ring, a 6-membered heteroaryl ring or a benzo ring, eachfused to a second ring. The second ring is a 5- or 6-membered monocyclicring which is saturated, partially unsaturated, or unsaturated, andcomprises a 5-membered heterocycle, a 6-membered heterocycle or acarbocycle (provided the first ring is not benzo when the second ring isa carbocycle).

The bicyclic heterocyclic group may be attached to its pendant group atany heteroatom or carbon atom which results in a stable structure. Thebicyclic heterocyclic group described herein may be substituted oncarbon or on a nitrogen atom if the resulting compound is stable. It ispreferred that when the total number of S and O atoms in the heterocycleexceeds 1, then these heteroatoms are not adjacent to one another. It ispreferred that the total number of S and O atoms in the heterocycle isnot more than 1. Examples of a bicyclic heterocyclic group are, but notlimited to, 1,2,3,4-tetrahydroquinolinyl,1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydro-quinolinyl,2,3-dihydro-benzofuranyl, chromanyl, 1,2,3,4-tetrahydro-quinoxalinyl,and 1,2,3,4-tetrahydro-quinazolinyl.

Bridged rings are also included in the definition of heterocycle. Abridged ring occurs when one or more, preferably one to three, atoms(i.e., C, O, N, or S) link two non-adjacent carbon or nitrogen atoms.Examples of bridged rings include, but are not limited to, one carbonatom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and acarbon-nitrogen group. It is noted that a bridge always converts amonocyclic ring into a tricyclic ring. When a ring is bridged, thesubstituents recited for the ring may also be present on the bridge.

As used herein, the term “heteroaryl” is intended to mean stablemonocyclic and polycyclic (including bicyclic and tricyclic) aromatichydrocarbons that include at least one heteroatom ring member such assulfur, oxygen, or nitrogen. Heteroaryl groups include, withoutlimitation, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl,pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl,benzodioxolanyl, and benzodioxane. Heteroaryl groups are substituted orunsubstituted. The nitrogen atom is substituted or unsubstituted (i.e.,N or NR wherein R is H or another substituent, if defined). The nitrogenand sulfur heteroatoms may optionally be oxidized (i.e., N→O andS(O)_(p), wherein p is 0, 1 or 2).

Examples of heteroaryl include, but are not limited to, acridinyl,azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,furanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl,imidazolopyridinyl, indolenyl, indolinyl, indolizinyl, indolyl,3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl,isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl,isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl,methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl,oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl,oxazolidinylperimidinyl, oxindolyl, pyrimidinyl, phenanthridinyl,phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathianyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl,pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl,pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl,pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,thianthrenyl, thiazolyl, thienyl, thiazolopyridinyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, andxanthenyl.

Examples of 5- to 10-membered heteroaryl include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrazolyl, imidazolyl, imidazolidinyl,indolyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, oxazolidinyl,thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, triazolyl,benzimidazolyl, 1H-indazolyl, benzofuranyl, benzothiofuranyl,benztetrazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl,benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl,isoquinolinyl, octahydroisoquinolinyl, isoxazolopyridinyl, quinazolinyl,quinolinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl,imidazolopyridinyl, and pyrazolopyridinyl. Examples of 5- to 6-memberedheterocycles include, but are not limited to, pyridinyl, furanyl,thienyl, pyrrolyl, pyrazolyl, pyrazinyl, imidazolyl, imidazolidinyl,indolyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, oxazolidinyl,thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, and triazolyl.

Unless otherwise indicated, “carbocyclyl” or “heterocyclyl” includes oneto three additional rings fused to the carbocyclic ring or theheterocyclic ring (such as aryl, cycloalkyl, heteroaryl orcycloheteroalkyl rings, for example,

and may be optionally substituted through available carbon atoms with 1,2, or 3 groups selected from hydrogen, halo, haloalkyl, alkyl,haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl,trifluoromethoxy, alkynyl, cycloalkyl-alkyl, cycloheteroalkyl,cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy,aryloxyalkyl, arylalkoxy, alkoxycarbonyl, arylcarbonyl, arylalkenyl,aminocarbonylaryl, arylthio, arylsulfinyl, arylazo, heteroarylalkyl,heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro,cyano, thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl,alkoxyarylthio, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl,arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy,arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl,arylsulfinylalkyl, arylsulfonylamino and arylsulfonaminocarbonyl and/orany of the alkyl substituents set out herein.

When any of the terms alkyl, alkenyl, alkynyl, cycloalkyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl are used as part of another group,the number of carbon atoms and ring members are the same as thosedefined in the terms by themselves. For example, alkoxy, haloalkoxy,alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy,alkoxyalkoxy, haloalkylamino, alkoxyalkylamino, haloalkoxyalkylamino,alkylthio, and the like each independently contains the number of carbonatoms which are the same as defined for the term “alkyl”, such as 1 to 4carbon atoms, 1 to 6 carbon atoms, 1 to 10 carbon atoms, etc. Similarly,cycloalkoxy, heterocyclyloxy, cycloalkylamino, heterocyclylamino,aralkylamino, arylamino, aryloxy, aralkyloxy, heteroaryloxy,heteroarylalkyloxy, and the like each independently contains ringmembers which are the same as defined for the terms “cycloalkyl”,“heterocyclyl”, “aryl”, and “heteroaryl”, such as 3 to 6-membered, 4 to7-membered, 6 to 10-membered, 5 to 10-membered, 5 or 6-membered, etc.

In accordance with a convention used in the art, a bond pointing to abold line, such as

as used in structural formulas herein, depicts the bond that is thepoint of attachment of the moiety or substituent to the core or backbonestructure.

In accordance with a convention used in the art, a wavy or squiggly bondin a structural formula, such as

is used to depict a stereogenic center of the carbon atom to which X′,Y′, and Z′ are attached and is intended to represent both enantiomers ina single FIGURE. That is, a structural formula with such as wavy bonddenotes each of the enantiomers individually, such as

as well as a racemic mixture thereof. When a wavy or squiggly bond isattached to a double bond (such as C═C or C═N) moiety, it include cis-or trans- (or E- and Z-) geometric isomers or a mixture thereof.

It is understood herein that if a carbocyclic or heterocyclic moiety maybe bonded or otherwise attached to a designated substrate throughdiffering ring atoms without denoting a specific point of attachment,then all possible points are intended, whether through a carbon atom or,for example, a trivalent nitrogen atom. For example, the terms“pyridinyl” and “pyridyl” mean 2-, 3- or 4-pyridinyl, the term “thienyl”means 2- or 3-thienyl, and so forth.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom in whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

One skilled in the art will recognize that substituents and othermoieties of the compounds of the present invention should be selected inorder to provide a compound which is sufficiently stable to provide apharmaceutically useful compound which can be formulated into anacceptably stable pharmaceutical composition. Compounds of the presentinvention which have such stability are contemplated as falling withinthe scope of the present invention.

The term “counter ion” is used to represent a negatively charged speciessuch as chloride, bromide, hydroxide, acetate, and sulfate. The term“metal ion” refers to alkali metal ions such as sodium, potassium orlithium and alkaline earth metal ions such as magnesium and calcium, aswell as zinc and aluminum.

As referred to herein, the term “substituted” means that at least onehydrogen atom (attached to carbon atom or heteroatom) is replaced with anon-hydrogen group, provided that normal valencies are maintained andthat the substitution results in a stable compound. When a substituentis oxo (i.e., ═O), then 2 hydrogens on the atom are replaced. Oxosubstituents are not present on aromatic moieties. When a ring system(e.g., carbocyclic or heterocyclic) is said to be substituted with acarbonyl group or a double bond, it is intended that the carbonyl groupor double bond be part (i.e., within) of the ring. Ring double bonds, asused herein, are double bonds that are formed between two adjacent ringatoms (e.g., C═C, C═N, or N═N). The term “substituted” in reference toalkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, alkylene, aryl,arylalkyl, heteroaryl, heteroarylalkyl, carbocyclyl, and heterocyclyl,means alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, alkylene, aryl,arylalkyl, heteroaryl, heteroarylalkyl, carbocyclyl, and heterocyclyl,respectively, in which one or more hydrogen atoms, which are attached toeither carbon or heteroatom, are each independently replaced with one ormore non-hydrogen substituent(s).

In cases wherein there are nitrogen atoms (e.g., amines) on compounds ofthe present invention, these may be converted to N-oxides by treatmentwith an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) toafford other compounds of this invention. Thus, shown and claimednitrogen atoms are considered to cover both the shown nitrogen and itsN-oxide (N→O) derivative.

When any variable occurs more than one time in any constituent orformula for a compound, its definition at each occurrence is independentof its definition at every other occurrence. Thus, for example, if agroup is shown to be substituted with 0, 1, 2, or 3 R groups, then saidgroup be unsubstituted when it is substituted with 0 R group, or besubstituted with up to three R groups, and at each occurrence R isselected independently from the definition of R.

Also, combinations of substituents and/or variables are permissible onlyif such combinations result in stable compounds.

As used herein, the term “tautomer” refers to each of two or moreisomers of a compound that exist together in equilibrium, and arereadily interchanged by migration of an atom or group within themolecule. For example, one skilled in the art would readily understandthat a 1,2,3-triazole exists in two tautomeric forms as defined above:

Thus, this disclosure is intended to cover all possible tautomers evenwhen a structure depicts only one of them.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms that are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, and/or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The compounds of the present invention can be present as salts, whichare also within the scope of this invention. Pharmaceutically acceptablesalts are preferred. As used herein, “pharmaceutically acceptable salts”refer to derivatives of the disclosed compounds wherein the parentcompound is modified by making acid or base salts thereof. Thepharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton,Pa. (1990), the disclosure of which is hereby incorporated by reference.

If the compounds of the present invention have, for example, at leastone basic center, they can form acid addition salts. These are formed,for example, with strong inorganic acids, such as mineral acids, forexample sulfuric acid, phosphoric acid or a hydrohalic acid, withorganic carboxylic acids, such as alkanecarboxylic acids of 1 to 4carbon atoms, for example acetic acid, which are unsubstituted orsubstituted, for example, by halogen as chloroacetic acid, such assaturated or unsaturated dicarboxylic acids, for example oxalic,malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, suchas hydroxycarboxylic acids, for example ascorbic, glycolic, lactic,malic, tartaric or citric acid, such as amino acids, (for exampleaspartic or glutamic acid or lysine or arginine), or benzoic acid, orwith organic sulfonic acids, such as (C₁-C₄) alkyl or arylsulfonic acidswhich are unsubstituted or substituted, for example by halogen, forexample methyl- or p-toluene-sulfonic acid. Corresponding acid additionsalts can also be formed having, if desired, an additionally presentbasic center. The compounds of the present invention having at least oneacid group (for example COOH) can also form salts with bases. Suitablesalts with bases are, for example, metal salts, such as alkali metal oralkaline earth metal salts, for example sodium, potassium or magnesiumsalts, or salts with ammonia or an organic amine, such as morpholine,thiomorpholine, piperidine, pyrrolidine, a mono, di or tri-loweralkylamine, for example ethyl, tert-butyl, diethyl, diisopropyl,triethyl, tributyl or dimethyl-propylamine, or a mono, di or trihydroxylower alkylamine, for example mono, di or triethanolamine. Correspondinginternal salts may furthermore be formed. Salts which are unsuitable forpharmaceutical uses but which can be employed, for example, for theisolation or purification of free compounds of Formula (I) or theirpharmaceutically acceptable salts, are also included.

Preferred salts of the compounds of Formula (I) which contain a basicgroup include monohydrochloride, hydrogensulfate, methanesulfonate,phosphate, nitrate or acetate.

Preferred salts of the compounds of Formula (I) which contain an acidgroup include sodium, potassium and magnesium salts and pharmaceuticallyacceptable organic amines.

In addition, the compounds of the present invention may have prodrugforms. Any compound that will be converted in vivo to provide thebioactive agent is a prodrug within the scope and spirit of theinvention. The term “prodrug” as used herein encompasses both theprodrugs based on the carboxylic acid residue, i.e., “prodrug esters”,and the prodrugs based on the arginine mimetics moiety, i.e., “prodrugsof arginine mimetics”. Such prodrugs are preferably administered orallysince hydrolysis in many instances occurs principally under theinfluence of the digestive enzymes. Parenteral administration may beused where the ester per se is active, or in those instances wherehydrolysis occurs in the blood.

The compounds of the present invention contain a carboxy group which canform physiologically hydrolyzable esters that serve as prodrugs, i.e.,“prodrug esters”, by being hydrolyzed in the body to yield the compoundsof the present invention per se. Examples of physiologicallyhydrolyzable esters of compounds of the present invention include C₁ toC₆ alkyl, C₁ to C₆ alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl,methoxymethyl, C₁₋₆ alkanoyloxy-C₁₋₆ alkyl (e.g., acetoxymethyl,pivaloyloxymethyl or propionyloxymethyl), C₁ to C₆ alkoxycarbonyloxy-C₁to C₆ alkyl (e.g., methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl,glycyloxymethyl, phenylglycyloxymethyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl), and other well knownphysiologically hydrolyzable esters used, for example, in the penicillinand cephalosporin arts. Such esters may be prepared by conventionaltechniques known in the art. The “prodrug esters” can be formed byreacting the carboxylic acid moiety of the compounds of the presentinvention with either alkyl or aryl alcohol, halide, or sulfonateemploying procedures known to those skilled in the art. Furthermore,various forms of prodrugs are well known in the art. For examples ofsuch prodrug derivatives, see:

Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985), and Widder, K.et al., eds., Methods in Enzymology, 112:309-396, Academic Press (1985);

Bundgaard, H., Chapter 5, “Design and Application of Prodrugs”,Krosgaard-Larsen, P. et al., eds., A Textbook of Drug Design andDevelopment, pp. 113-191, Harwood Academic Publishers (1991);

Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992);

Bundgaard, H. et al., J. Pharm. Sci., 77:285 (1988); and

Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984).

Preparation of prodrugs is well known in the art and described in, forexample, King, F. D., ed., Medicinal Chemistry: Principles and Practice,The Royal Society of Chemistry, Cambridge, UK (1994); Testa, B. et al.,Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry andEnzymology, VCHA and Wiley-VCH, Zurich, Switzerland (2003); Wermuth, C.G., ed., The Practice of Medicinal Chemistry, Academic Press, San Diego,Calif. (1999); Rautio, J. et al., Nature Review Drug Discovery, 17,559-587, (2018).

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include deuterium(symbol D or ²H) and tritium (symbol T or ³H). Isotopes of carboninclude ¹³C and ¹⁴C. Isotopically-labeled compounds of the invention cangenerally be prepared by conventional techniques known to those skilledin the art or by processes analogous to those described herein, using anappropriate isotopically-labeled reagent in place of the non-labeledreagent otherwise employed. Such compounds have a variety of potentialuses, e.g., as standards and reagents in determining the ability of apotential pharmaceutical compound to bind to target proteins orreceptors, or for imaging compounds of this invention bound tobiological receptors in vivo or in vitro.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. It is preferred that compounds of thepresent invention do not contain a N-halo, S(O)₂H, or S(O)H group.

The term “solvate” means a physical association of a compound of thisinvention with one or more solvent molecules, whether organic orinorganic. This physical association includes hydrogen bonding. Thesolvent molecules in the solvate may be present in a regular arrangementand/or a non-ordered arrangement. The solvate may comprise either astoichiometric or nonstoichiometric amount of the solvent molecules.“Solvate” encompasses both solution-phase and isolable solvates.Exemplary solvates include, but are not limited to, hydrates,ethanolates, methanolates, and isopropanolates. Methods of solvation aregenerally known in the art.

The term “glycosyl” means a monovalent free radical or substituentmoiety obtained by removing the hemiacetal hydroxyl group from thecyclic form of a monosaccharide and, by extension, of a loweroligosaccharide. In one embodiment, the glycosyl group has the followingstructure:

Abbreviations as used herein, are defined as follows: “1×” for once,“2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “eq” forequivalent or equivalents, “g” for gram or grams, “mg” for milligram ormilligrams, “L” for liter or liters, “mL” for milliliter or milliliters,“μL” for microliter or microliters, “N” for normal, “M” for molar,“mmol” for millimole or millimoles, “min” for minute or minutes, “h” forhour or hours, “rt” for room temperature, “RBF” for round bottom flask,“atm” for atmosphere, “psi” for pounds per square inch, “conc.” forconcentrated, “RCM” for ring-closing metathesis, “sat” or “sat'd” forsaturated, “SFC” for supercritical fluid chromatography, “MW” formolecular weight, “mp” for melting point, “ee” for enantiomeric excess,“MS” or “Mass Spec” for mass spectrometry, “ESI” for electrosprayionization mass spectroscopy, “HR” for high resolution, “HRMS” for highresolution mass spectrometry, “LCMS” for liquid chromatography massspectrometry, “HPLC” for high pressure liquid chromatography, “RP HPLC”for reverse phase HPLC, “TLC” or “tlc” for thin layer chromatography,“NMR” for nuclear magnetic resonance spectroscopy, “nOe” for nuclearOverhauser effect spectroscopy, “¹H” for proton, “δ” for delta, “s” forsinglet, “d” for doublet, “t” for triplet, “q” for quartet, “m” formultiplet, “br” for broad, “Hz” for hertz, and “α”, “β”, “R”, “S”, “E”,and “Z” are stereochemical designations familiar to one skilled in theart.

Abbreviations

Furthermore, the following abbreviations are employed in the Schemes,Examples and elsewhere herein:

-   Me methyl-   Et ethyl-   Pr propyl-   i-Pr isopropyl-   Bu butyl-   i-Bu isobutyl-   t-Bu tert-butyl-   Ph phenyl-   Bn benzyl-   Boc or BOC tert-butyloxycarbonyl-   Boc₂O di-tert-butyl dicarbonate-   ACN acetonitrile-   AcOH or HOAc acetic acid-   AlCl₃ aluminum chloride-   AIBN azobisisobutyronitrile-   BBr₃ boron tribromide-   BCl₃ boron trichloride-   BEMP    2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine-   BOP reagent benzotriazol-1-yloxytris(dimethylamino)phosphonium    hexafluorophosphate-   Burgess reagent 1-methoxy-N-triethylammoniosulfonyl-methanimidate-   CBz carbobenzyloxy-   DCM or CH₂Cl₂ dichloromethane-   CH₃CN or ACN acetonitrile-   CDCl₃ deutero-chloroform-   CHCl₃ chloroform-   mCPBA or m-CPBA meta-chloroperbenzoic acid-   Cs₂CO₃ cesium carbonate-   Cu(OAc)₂ copper (II) acetate-   Cy₂NMe N-cyclohexyl-N-methylcyclohexanamine-   DBU 1,8-diazabicyclo[5.4.0]undec-7-ene-   DCE 1,2 dichloroethane-   DEA diethylamine-   DMP or Dess-Martin    1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-beniziodoxol-3-(1H)-one    Periodinane-   DIC or DIPCDI diisopropylcarbodiimide-   DIEA, DIPEA or diisopropylethylamine-   Hunig's base-   DMAP 4-dimethylaminopyridine-   DME 1,2-dimethoxyethane-   DMF dimethyl formamide-   DMSO dimethyl sulfoxide-   cDNA complimentary DNA-   Dppp (R)-(+)-1,2-bis(diphenylphosphino)propane-   DuPhos (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene-   EDC N-(3-dimthylaminopropyl)-N′-ethylcarbodiimide-   EDCI N-(3-dimthylaminopropyl)-N′-ethylcarbodiimide hydrochloride-   EDTA ethylenediaminetetraacetic acid-   (S,S)-EtDuPhosRh(I)    (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene(1,5-cyclooctadiene)rhodium(I)    trifluoromethanesulfonate-   Et₃N or TEA triethylamine-   EtOAc ethyl acetate-   Et₂O diethyl ether-   EtOH ethanol-   GMF glass microfiber filter-   Grubbs II    (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro    phenylmethylene)(triycyclohexylphosphine)ruthenium-   HCl hydrochloric acid-   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HEPES 4-(2-hydroxyethyl)piperaxine-1-ethanesulfonic acid-   Hex hexanes-   HOBt or HOBT 1-hydroxybenzotriazole-   H₂O₂ hydrogen peroxide-   IBX 2-iodoxybenzoic acid-   H2SO₄ sulfuric acid-   Jones reagent CrO₃ in aqueous H₂SO₄, 2 M-   K₂CO₃ potassium carbonate-   K₂HPO₄ potassium phosphate dibasic-   KOAc potassium acetate-   K₃PO₄ potassium phosphate-   LAH lithium aluminum hydride-   LG leaving group-   LiOH lithium hydroxide-   MeOH methanol-   MgSO₄ magnesium sulfate-   MsCl methanesulfonyl chloride-   MsOH or MSA methylsulfonic acid-   NaCl sodium chloride-   NaH sodium hydride-   NaHCO₃ sodium bicarbonate-   Na₂CO₃ sodium carbonate-   NaOH sodium hydroxide-   Na₂SO₃ sodium sulfite-   Na₂SO₄ sodium sulfate-   NBS N-bromosuccinimide-   NCS N-chlorosuccinimide-   NH₃ ammonia-   NH₄Cl ammonium chloride-   NH₄OH ammonium hydroxide-   NH₄COOH ammonium formate-   NMM N-methylmorpholine-   OTf triflate or trifluoromethanesulfonate-   Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0)-   Pd(OAc)₂ palladium(II) acetate-   Pd/C palladium on carbon-   Pd(dppf)Cl₁    [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II)-   Ph₃PCl₂ triphenylphosphine dichloride-   PG protecting group-   POCl₃ phosphorus oxychloride-   PPTS pyridinium p-toluenesulfonate-   i-PrOH or IPA isopropanol-   PS Polystyrene-   PtO₂ platinum oxide-   rt room temperature-   RuPhos-Pd-G2    chloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)-   SEM-Cl 2-(trimethysilyl)ethoxymethyl chloride-   SiO₂ silica oxide-   SnCl₂ tin(II) chloride-   TBAI tetra-n-butylammonium iodide-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   TMSCHN₂ trimethylsilyldiazomethane-   T3P propane phosphonic acid anhydride-   TRIS tris (hydroxymethyl) aminomethane-   pTsOH p-toluenesulfonic acid-   TsCl p-tolunesulfonyl chloride

IV. Methods of Preparation

The compounds of the present invention can be prepared in a number ofways well known to one skilled in the art of organic synthesis using themethods described below, together with synthetic methods known in theart of synthetic organic chemistry, or variations thereon as appreciatedby those skilled in the art. Preferred methods include, but are notlimited to, those described below. All references cited herein arehereby incorporated in their entirety by reference. The reactions areperformed in a solvent or solvent mixture appropriate to the reagentsand materials employed and suitable for the transformations beingaffected. It will be understood by those skilled in the art of organicsynthesis that the functionality present on the molecule should beconsistent with the transformations proposed. This will sometimesrequire a judgment to modify the order of the synthetic steps or toselect one particular process scheme over another in order to obtain adesired compound of the invention. Restrictions to the substituents thatare compatible with the reaction conditions will be readily apparent toone skilled in the art and alternate methods must then be used. It willalso be recognized that another major consideration in the planning ofany synthetic route in this field is the judicious choice of theprotecting group used for protection of the reactive functional groupspresent in the compounds described in this invention. A particularlyuseful compendium of synthetic methods which may be applicable to thepreparation of compounds of the present invention may be found inLarock, R. C., Comprehensive Organic Transformations, VCH, New York(1989).

The compounds of the present invention may be prepared using thereactions and techniques described in this section. The reactions areperformed in solvents appropriate to the reagents and materials employedand are suitable for the transformations being effected. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including solvent,reaction atmosphere, reaction temperature, duration of the experimentand workup procedures, are chosen to be the conditions standard for thatreaction, which should be readily recognized by one skilled in the art.One skilled in the art of organic synthesis understands that thefunctionality present on various portions of the edict molecule must becompatible with the reagents and reactions proposed. Not all compoundsof Formula (I) falling into a given class may be compatible with some ofthe reaction conditions required in some of the methods described. Suchrestrictions to the substituents, which are compatible with the reactionconditions, will be readily apparent to one skilled in the art andalternate methods must be used. A particularly useful compendium ofsynthetic methods which may be applicable to the preparation ofcompounds of the present invention may be found in Larock, R. C.,Comprehensive Organic Transformations, VCH, New York (1989).

Generic Schemes

Compounds of the present invention, represented by Formula (I), Formula(II), or any subgenera or species thereof, can be prepared according tothe general routes shown in SCHEMES 1 to 5 below.

Scheme 1 describes a method of preparing compounds of Formula I-a, I-band I-c, a subset of Formula I. Reduction of the ester intermediate 1can be accomplished by a number of reagents including, but not limitedto LiAlH₄, DIBAL-H, or LiBH₄ in an appropriate solvent such as Et₂O orTHF to give primary alcohol intermediate 2. The resulting hydroxyl ofintermediate 2 can be converted to halogenated intermediate 3 by theAppel reaction (PPh₃, CX₄) in a solvent such as, but not limited todichloromethane, or by heating 2 with aqueous HBr, or HCl in a solventsuch as, but not limited to DCE. Intermediate 3 can be converted to thecorresponding phosphonium 4 by the reaction of the halide 3 withreagents such as, but not limited to PPh₃ in a refluxing solvent such astoluene. Wittig olefination between phosphonium 4 and ketone or aldehyde5 (commercially available or readily prepared by methods known to oneskilled in the art) can be used to obtain an E-Z mixture of alkene 6under conditions that include treatment of phosphonium 4 with a basesuch as, but not limited to, LiHMDS, LDA, NaH, KOtBu, or nBuLi followedby addition of 5 in a suitable solvent such as THF. The olefin isomerscan typically be separated by SiO₂ or C-18 reverse phase chromatography.Alternatively, heating 3 neat in a trialkoxy phosphite such as, but notlimited to, triethoxy phosphite can yield the corresponding phosphonate4. Homer-Wadsworth-Emmons (HWE) olefination can be employed to couple 4and 5 under conditions similar to those described for Wittingolefination. The alkene 6 obtained under HWE olefination conditionstypically favors formation of the E isomer and if a mixture of E-Zisomers is obtained they can likewise be separated by SiO₂ or C-18reverse phase chromatography. Removal of the protecting group P* can beaccomplished by a variety of conditions that will vary depending on thenature of P* and on compatibility with other functional groups presentin 6. In most examples P*=Boc, and appropriately acidic conditions (i.e.TFA, HCl) can be used to facilitate removal of the protecting group togive intermediate 7. However, if alternative protecting groups arerequired for functional group compatibility, then they can be removed bymethods known to one skilled in the art. Additional methods forprotecting group removal may be found in Greene, T. and Wuts, P. G. M.,Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc., NewYork, N.Y., 2006 and references therein. Intermediate 7 can be convertedto products I-a through coupling with X⁶-L¹-Z—R^(x) (commerciallyavailable or readily prepared by methods known to one skilled in theart, where X⁶ represents a halide, triflate or equivalent) underconditions that are well-known to one skilled in the art. The productsI-a can be obtained through a variety of C—N bond forming reactionsbetween intermediate 1 and a suitable aryl halide, triflate orequivalent. Some examples include, but are not limited to, Pd-catalyzedBuchwald-Hartwig reaction, Cu-mediated Ullmann coupling, Ni-mediatedamination, or nucleophilic aromatic substitution (SNAr). Alternatively,the Cu-catalyzed Chan-Evans-Lam coupling can be employed if X⁶represents a boronic acid or ester which can be commercially availableor obtained by borylation of the corresponding aryl halide. In eachcase, optimization of variables for the coupling reaction such ascatalyst, ligand, solvent, base, additives and temperature may berequired. If I-a contains an ester or nitrile it can be hydrolyzed tothe corresponding carboxylic acid I-b under conditions such as but notlimited to treatment with NaOH or LiOH in solvents consisting of MeOH,THF, and water at a temperature suitable to enable the hydrolysis.Acid-mediated hydrolysis of particular esters, such as a tert-butylester, may be required in some cases to obtain I-b. Examples I-c can beobtained by the coupling of I-b with R⁷—N—R⁸ (commercially available orreadily prepared by methods known to one skilled in the art) utilizingcoupling reagents such as but not limited to, T3P, EDC, DCC or CDI inthe presence of a suitable base, for example triethylamine, Hunig'sbase, or pyridine with or without additives such as HOBT or DMAP in anappropriate solvent such as dichloromethane, ethyl acetate, DMF or THF.In each case the specific conditions utilized to obtain I-c, includingtemperature and concentration, may require optimization.

Scheme 2 describes a method for preparing intermediate 1a, a subset ofintermediate 1. Aldehydes 8 (commercially available or readily preparedby methods known to one skilled in the art) can be condensed withhydroxylamine hydrochloride under a variety of conditions including, butnot limited to, stirring both reactants in pyridine at room temperature,or gently heating the reactants in the presence of a base like sodiumhydroxide or sodium acetate in a suitable solvent such as ethanol. Theresultant oximes can be converted to the corresponding hydroximoylhalides 9 through halogenation by reagents such as but not limited toNCS or NBS in a suitable solvent such as DMF. Hydroximoyl halides 9 canbe reacted with β-ketoesters (commercially available or readily preparedby methods known to one skilled in the art) in the presence of triethylamine or another suitable base in a solvent such as, but not limited to,dichloromethane to give 3,4,5-substituted isoxalole ester intermediate1a.

Scheme 3 describes a method for preparing intermediate 2b, a subset ofintermediate 2. The synthesis can commence with azidation of amine 10a(commercially available or readily prepared by methods known to oneskilled in the art) under conditions such as, but not limited to,treatment with sodium nitrite in acidic media (H₂O/TFA) followed byaddition of sodium azide in an appropriate solvent, such as water at asuitable temperature to give azide 11. Alternatively, azide 11 can beobtained by the heating of halide 10b (commercially available or readilyprepared by methods known to one skilled in the art) with an azide salt,such as sodium azide, in a mixture of DMSO/water at an appropriatetemperature. The resultant azide 11 can undergo cyclization with analkyne 12 by heating the reactants in a solvent such as toluene to give1b. Alkynes 12 are commercially available, or can be obtained by avariety of methods including, but not limited to, the deprotonation ofthe corresponding terminal alkyne and trapping the resulting anion withformaldehyde or a formaldehyde equivalent.

Scheme 4 describes a method for preparing intermediate 1c, a subset ofintermediate 1. α-Ketoesters 13 (commercially available or readilyprepared by methods known to one skilled in the art) can be condensedwith N,N-dimethylformamide dimethyl acetal 14 by heating in a suitablesolvent such as EtOH or MeOH to give intermediate 15. Hydrazines 16 canundergo annulation with intermediates 15 to give intermediates 1c byheating the two reactants in an appropriate solvent such as EtOH orMeOH. Hydrazines 16 are commercially available or can be prepared by thetreatment of the corresponding amine with a reagent such as, but notlimited to sodium nitrite in acidic media, or the coupling of thecorresponding aryl halide with hydrazine.

Scheme 5 describes a method for preparing intermediate 2a, a subset ofintermediate 2. An appropriately substituted boronic acid or ester 17(commercially available or readily prepared by methods known to oneskilled in the art) and a pyrazole 18 bearing a suitably reactivehalogen or equivalent X, (commercially available or readily prepared bymethods known to one skilled in the art) can be coupled through thePd-catalyzed Suzuki reaction to give intermediate 19. Typical conditionsfor the Suzuki coupling include, but are not limited to, heating thereactants 17 and 18 together with a palladium catalyst, ligand and baseat a suitable temperature in a deoxygenated solvent or solvent mixture.Specific conditions include, but are not limited to PdCl₂(dppf)₂, Na₂CO₃in THF/water at 120° C. In each case the specific conditions utilized toobtain 19, including stoichiometry, palladium source, ligand, base,solvent, temperature, and concentration may require independentoptimization. The coupling partners 17 and 18, are either commerciallyavailable or can be readily prepared by methods known to one skilled inthe art. Intermediate 19 can be deprotonated at the 5-position of thepyrazole by a sufficiently strong base such as, but not limited to,n-BuLi, or LDA in a suitable solvent such as THF or Et₂O. The resultinganion from deprotonation of 19 can be trapped in situ with a formylequivalent such as DMF to yield aldehyde intermediate 20. Reduction ofthe aldehyde 20 can be accomplished by a number of reagents including,but not limited to LiAlH₄, DIBAL-H, or LiBH₄ in an appropriate solventsuch as, but not limited to, THF or Et₂O to give intermediate 2a.

EXAMPLES

The following Examples are offered as illustrative, as a partial scopeand particular embodiments of the invention and are not meant to belimiting of the scope of the invention. Abbreviations and chemicalsymbols have their usual and customary meanings unless otherwiseindicated. Unless otherwise indicated, the compounds described hereinhave been prepared, isolated and characterized using the schemes andother methods disclosed herein or may be prepared using the same.

As appropriate, reactions were conducted under an atmosphere of drynitrogen (or argon). For anhydrous reactions, DRISOLV® solvents from EMwere employed. For other reactions, reagent grade or HPLC grade solventswere utilized. Unless otherwise stated, all commercially obtainedreagents were used as received.

HPLC/MS and Preparatory/Analytical HPLC Methods Employed inCharacterization or Purification of Examples

NMR (nuclear magnetic resonance) spectra were typically obtained onBruker or JEOL 400 MHz and 500 MHz instruments in the indicatedsolvents. All chemical shifts are reported in ppm from tetramethylsilanewith the solvent resonance as the internal standard. ¹HNMR spectral dataare typically reported as follows: chemical shift, multiplicity(s=singlet, br s=broad singlet, d=doublet, dd=doublet of doublets,t=triplet, q=quartet, sep=septet, m=multiplet, app=apparent), couplingconstants (Hz), and integration.

The term HPLC refers to a Shimadzu high performance liquidchromatography instrument with one of following methods:

General Method A Example 1(E)-6-(4-(2-(5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)nicotinic acid

Step 1. 2,6-Dichlorobenzaldehyde oxime

Hydroxylamine hydrochloride (6.6 g, 95 mmol) was added to a roomtemperature solution of 2,6-dichlorobenzaldehyde (11.1 g, 63.4 mmol) inpyridine (31.7 mL) giving a mild exotherm. After 10 minutes the excesspyridine was removed in vacuo and the residue was partitioned betweenEt₂O and water. The organic layer was sequentially washed with saturatedaqueous NH₄Cl, brine and the combined aqueous layers were back extractedwith several small portions of Et₂O. The combined organic extracts weredried over Na₂SO₄, filtered and concentrated in vacuo to give2,6-dichlorobenzaldehyde oxime (12.4 g, 65.3 mmol, 100% yield) as awhite solid. The product was carried on to the next step without furtherpurification. ¹H NMR (400 MHz, CDCl₃) δ 8.39 (s, 1H), 7.92 (s, 1H),7.40-7.36 (m, 2H), 7.27-7.22 (m, 1H).

Step 2. 2,6-Dichloro-N-hydroxybenzimidoyl chloride

2,6-Dichlorobenzaldehyde oxime (12.0 g, 63.1 mmol) was dissolved in DMF(45.9 mL) and heated to 40° C. NCS (10.1 g, 76.0 mmol) dissolved in DMF(38.3 mL) was added to the warm solution over the space of approximately3 minutes. After stirring overnight the reaction mixture was cooled toroom temperature, poured into ice, and extracted with Et₂O. The organiclayer was collected and washed with brine. The combined aqueous layerswere back extracted with Et₂O. The combined organic layers were driedover Na₂SO₄, filtered and concentrated to dryness in vacuo. The residuewas purified by flash chromatography on SiO₂ (0-50% EtOAc/hexanes, Isco120 g column) to give 2,6-dichloro-N-hydroxybenzimidoyl chloride (13.3g, 59.3 mmol, 94% yield) as a waxy white solid. ¹H NMR (500 MHz, CDCl₃)δ 8.02 (s, 1H), 7.43-7.37 (m, 2H), 7.37-7.30 (m, 1H).

Step 3. Methyl5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carboxylate

To a 50 mL round bottom flask containing methyl3-cyclopropyl-3-oxopropanoate (1.3 g, 8.9 mmol) was added triethylamine(2.5 mL, 17.8 mmol). The resulting clear solution was stirred at roomtemperature for 15 minutes and was cooled in an ice water bath. To thestirring solution was added a solution of2,6-dichloro-N-hydroxybenzimidoyl chloride (2.0 g, 8.9 mmol) in EtOH (4mL) over the space of 10 minutes giving a white suspension. Afterstirring at room temperature overnight, the reaction mixture wasconcentrated in vacuo and the residue was purified by flashchromatography on SiO₂ (0-10% EtOAc/hexanes, Isco 80 g column) to givemethyl 5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carboxylate (2.4g, 7.7 mmol, 87% yield) as a white solid. ¹H NMR (500 MHz, CDCl₃) δ7.45-7.39 (m, 2H), 7.39-7.33 (m, 1H), 3.71 (s, 3H), 2.93 (tt, J=8.5, 5.2Hz, 1H), 1.47-1.40 (m, 2H), 1.34-1.27 (m, 2H).

Step 4. (5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methanol

To a solution of methyl5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carboxylate (3.0 g, 9.6mmol) in THF (11.1 mL) at 0° C. was added 1 M diisobutyl aluminumhydride (20.2 mL, 20.2 mmol) in toluene. The reaction mixture was warmedto room temperature and stirred for 2 h. The reaction was cooled to 0°C. and quenched by the addition of MeOH (2 mL) and 1 M aq. HCl (˜75 mL).The mixture was then extracted with EtOAc, and the organic layer waswashed with brine. The organic layer was dried over MgSO₄ andconcentrated to give(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methanol (2.5 g, 8.9mmol, 92% yield) as a white solid, which was used without furtherpurification. ¹H NMR (500 MHz, CDCl₃) δ 7.46 (d, J=1.1 Hz, 1H), 7.45 (s,1H), 7.41-7.36 (m, 1H), 4.44 (s, 2H), 2.22 (tt, J=8.5, 5.2 Hz, 1H), 1.42(br s, 1H), 1.35-1.25 (m, 2H), 1.23-1.11 (m, 2H).

Step 5. 5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carbaldehyde

To a solution of(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methanol (2.1 g, 7.4mmol) in dichloromethane (37.0 mL) was added a mixture of pyridiniumchlorochromate (6.4 g, 29.6 mmol) and finely ground 3 Å molecular sieves(6.1 g). The resulting mixture was stirred at room temperature for 30min and then filtered through a pad of Celite. The pad was washed withMeOH/DCM. The filtrate was evaporated and the residue was purified byflash chromatography on SiO₂ (0-100% EtOAc/hexanes, Isco 80 g column) togive 5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carbaldehyde (1.9g, 6.8 mmol, 93% yield) as a white solid. ¹H NMR (500 MHz, CDCl₃) δ 9.67(s, 1H), 7.49-7.44 (m, 2H), 7.43-7.37 (m, 1H), 2.82 (tt, J=8.3, 5.2 Hz,1H), 1.52-1.45 (m, 2H), 1.40-1.33 (m, 2H).

Step 6. 4-(bromomethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole

Tetrabromomethane (3.8 g, 11.4 mmol) dissolved in dichloromethane (5.1mL) was added to a 0° C. solution of(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methanol (2.2 g, 7.6mmol) and triphenylphosphine (3.0 g, 11.4 mmol) in dichloromethane (25.2mL). The reaction mixture was allowed to warm to room temperature andstirred for 2 h. The reaction mixture was diluted with dichloromethaneand washed with H₂O. The dichloromethane layer was concentrated in vacuoto dryness. The resulting residue was purified by flash chromatographyon SiO₂ (0-20% EtOAc/hexanes, Isco 120 g column) to give4-(bromomethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (2.3 g,6.7 mmol, 89% yield) as a white solid. ¹H NMR (500 MHz, CDCl₃) δ7.49-7.42 (m, 2H), 7.42-7.36 (m, 1H), 4.23 (s, 2H), 2.14 (tt, J=8.4, 5.1Hz, 1H), 1.33-1.29 (m, 2H), 1.23-1.17 (m, 2H).

Step 7. Diethyl((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)phosphonate

Triethyl phosphite (1.1 mL, 6.2 mmol) was added to a solution of4-(bromomethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (1.2 g,3.5 mmol) in dioxane (1.7 mL). The reaction mixture was stirred at 120°C. overnight. The reaction mixture was loaded onto SiO₂ and purified byflash chromatography on SiO₂ (0-100% EtOAc/hexanes, Isco 40 g column) togive diethyl((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)phosphonate(1.4 g, 3.4 mmol, 98% yield) as a white solid. ¹H NMR (500 MHz, CDCl₃) δ7.46-7.40 (m, 2H), 7.38-7.31 (m, 1H), 4.08-3.86 (m, 4H), 2.97-2.79 (m,2H), 2.28-2.17 (m, 1H), 1.25 (dd, J=5.0, 2.2 Hz, 2H), 1.22 (t, J=7.0 Hz,6H), 1.16-1.09 (m, 2H).

Step 8. tert-Butyl(E)-4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidine-1-carboxylate

To a solution of diethyl((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl) methyl)phosphonate(0.56 g, 1.4 mmol) in THF (11.0 mL) at −78° C. under nitrogenatmosphere, was added LiHMDS (1.0 M in THF) (2.7 mL, 2.7 mmol) dropwise.The mixture was stirred for 30 minutes and a solution of tert-butyl4-formylpiperidine-1-carboxylate (0.29 g, 1.4 mmol) in THF (2.0 mL) wasadded. The reaction mixture was allowed to warm up to room temperatureand stirred for 5 h. The reaction was quenched with 0.2 mL of MeOH,filtered through a pad of SiO₂ gel and concentrated to dryness in vacuo.The residue was purified by flash chromatography on SiO₂ (0-100%EtOAc/hexanes) to give tert-butyl(E)-4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidine-1-carboxylate(339 mg, 0.73 mmol, 54% yield) as a soft solid. ¹H NMR (400 MHz, CDCl₃)δ 7.44-7.41 (m, 2H), 7.39-7.33 (m, 1H), 6.04 (dd, J=16.2, 1.2 Hz, 1H),5.41 (dd, J=16.3, 7.0 Hz, 1H), 4.00 (br d, J=10.6 Hz, 2H), 2.72 (br t,J=12.1 Hz, 2H), 2.17-2.03 (m, 2H), 1.61 (br s, 1H), 1.57 (s, 2H), 1.45(s, 9H), 1.32-1.21 (m, 2H), 1.17-1.06 (m, 3H).

9.(E)-5-Cyclopropyl-3-(2,6-dichlorophenyl)-4-(2-(piperidin-4-yl)vinyl)isoxazole

To a solution of (E)-tert-butyl4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidine-1-carboxylate(0.16 g, 0.35 mmol) in dichloromethane (0.6 mL) at 0° C. was added TFA(0.14 mL, 1.75 mmol) dropwise. The mixture was stirred at 0° C. for 30minutes and at room temperature overnight. The excess TFA was removed invacuo, the residue cooled to 0° C., basified with 1 N NaOH and extractedwith three small portions of EtOAc. The extracts were washed with brine,dried over MgSO₄, filtered and concentrated in vacuo to give(E)-5-cyclopropyl-3-(2,6-dichlorophenyl)-4-(2-(piperidin-4-yl)vinyl)isoxazole(0.11 g, 0.29 mmol, 83% yield) as a light-yellow sticky solid. Theproduct was used without further purification.

General Method for S_(N)AR: Method A1 Example 1.(E)-6-(4-(2-(5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)nicotinicacid

A mixture of(E)-5-cyclopropyl-3-(2,6-dichlorophenyl)-4-(2-(piperidin-4-yl)vinyl)isoxazole (18.2 mg, 0.050 mmol), methyl 6-fluoronicotinate (15.5 mg,0.10 mmol) and cesium carbonate (49.0 mg, 0.15 mmol) in DMA (0.5 mL) washeated at 60° C. After heating for 2 h, the mixture was cooled to roomtemperature and purified by flash chromatography on SiO₂ (0-100%EtOAc/hexanes, Isco 12 g column). The desired fractions were combinedand evaporated in vacuo to give (E)-methyl6-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)nicotinate(20 mg, 0.040 mmol, 80% yield) as an off-white solid. ¹H NMR (500 MHz,CDCl₃) δ 8.77 (d, J=2.2 Hz, 1H), 7.98 (dd, J=9.1, 2.5 Hz, 1H), 7.45-7.38(m, 2H), 7.37-7.30 (m, 1H), 6.56 (d, J=9.1 Hz, 1H), 6.07 (d, J=16.2 Hz,1H), 5.43 (dd, J=16.2, 6.9 Hz, 1H), 4.37 (br d, J=13.2 Hz, 2H), 3.86 (s,3H), 3.02-2.90 (m, 2H), 2.29 (dtd, J=10.9, 7.2, 3.6 Hz, 1H), 2.15-2.05(m, 1H), 1.80-1.69 (m, 2H), 1.36-1.20 (m, 4H), 1.18-1.07 (m, 2H).

A mixture of (E)-methyl6-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)nicotinate(20 mg, 0.040 mmol) and 1M aqueous lithium hydroxide, (140 μL, 0.14mmol) in THF (268 μL) and MeOH (134 μL) was stirred at room temperature.After stirring at room temperature overnight, the mixture wasconcentrated in vacuo to remove the solvents, cooled to 0° C. andacidified with 1N HCl. The mixture was evaporated in vacuo, dissolved in1:1 DMF/DMSO (2 mL) and the crude material was purified via preparativeLC/MS with the following conditions: Column: XBridge C18, 19×200 mm,5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mMammonium acetate; Gradient: 10-80% B over 19 minutes, then a 5-minutehold at 100% B; Flow: 20 mL/min. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to give(E)-6-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)nicotinicacid (13.9 mg, 0.028 mmol, 69% yield). MS (ESI) m/z: 484.3 [M+H]+; ¹HNMR (500 MHz, DMSO-d₆) δ 8.57 (d, J=2.3 Hz, 1H), 7.88 (dd, J=2.4, 9.1Hz, 1H), 7.64 (d, J=8.0 Hz, 2H), 7.57 (dd, J=7.0, 9.0 Hz, 1H), 6.79 (d,J=9.2 Hz, 1H), 6.15 (d, J=16.3 Hz, 1H), 5.30 (dd, J=7.0, 16.2 Hz, 1H),4.28 (d, J=13.3 Hz, 2H), 2.93 (t, J=12.4 Hz, 2H), 2.33 (dq, J=4.3, 5.0,8.5 Hz, 1H), 1.60 (d, J=12.9 Hz, 2H), 1.23-0.99 (m, 6H); HLE GAL-FXREC₅₀=14 nM.

General Method for Pd-Catalyzed C—N Coupling: Method A2 Example 2(E)-6-(4-(2-(5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)-1-methyl-1H-indole-3-carboxylicacid

A slurry of(E)-5-cyclopropyl-3-(2,6-dichlorophenyl)-4-(2-(piperidin-4-yl)vinyl)isoxazole (16.2 mg, 0.045 mmol), methyl6-bromo-1-methyl-1H-indole-3-carboxylate (14.4 mg, 0.054 mmol) andCs₂CO₃ (29.1 mg, 0.089 mmol) in dioxane (446 μL) was degassed bybubbling nitrogen through the mixture for 5 minutes.Chloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(RuPhos-Pd-G2) (1.7 mg, 2.2 μmol) was then added and the reaction vesselwas sealed and heated to 90° C. After heating for 2 days, the mixturewas diluted with MeOH, filtered and concentrated to dryness in vacuo. Tothe residue was added THF (300 μL), MeOH (150 μL) and 1M aqueous lithiumhydroxide (180 μL, 0.18 mmol) and the resulting mixture was stirred atroom temperature overnight. The mixture was heated at 50° C. for 10 h,and at 65° C. for 3 h. The mixture was concentrated to remove thesolvents, cooled to 0° C. and acidified with 1 N HCl. The mixture wasdissolved in DMSO (2 mL), filtered and the crude material was purifiedvia preparative LC/MS with the following conditions: Column: XBridgeC18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10-mM ammonium acetate; Gradient: 45-90% B over 22 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and dried via centrifugal evaporation togive(E)-6-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)-1-methyl-1H-indole-3-carboxylicacid (5.3 mg, 9.9 μmol, 22% yield). MS (ESI) m/z: 536.1 [M+H]+; ¹H NMR(500 MHz, DMSO-d₆) δ 7.84-7.76 (m, 2H), 7.68 (d, J=8.0 Hz, 2H), 7.60(dd, J=7.1, 9.1 Hz, 1H), 6.97-6.85 (m, 2H), 6.20 (d, J=16.2 Hz, 1H),5.37 (dd, J=7.0, 16.2 Hz, 1H), 3.76 (s, 3H), 3.56 (d, J=12.0 Hz, 2H),2.68 (t, J=11.5 Hz, 2H), 2.37 (q, J=3.4, 5.5 Hz, 1H), 2.15 (br s, 1H),1.67 (d, J=12.7 Hz, 2H), 1.39-0.97 (m, 6H); HLE GAL-FXR EC₅₀=5 nM.

Example 3(Z)-6-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)nicotinicacid

Step 1.(Z)-4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidine-1-carboxylate

The title compound was obtained as a minor isolate from General MethodA, step 8. ¹H NMR (500 MHz, CDCl₃) δ 7.42-7.39 (m, 2H), 7.34-7.30 (m,1H), 5.89 (d, J=11.3 Hz, 1H), 5.48 (t, J=10.7 Hz, 1H), 4.00 (br s, 2H),2.36-2.21 (m, 1H), 1.98 (tt, J=8.5, 5.0 Hz, 1H), 1.44 (s, 9H), 1.29-1.23(m, 3H), 1.21-1.12 (m, 4H), 1.12-1.05 (m, 2H).

Step 2.(Z)-5-Cyclopropyl-3-(2,6-dichlorophenyl)-4-(2-(piperidin-4-yl)vinyl)isoxazole

To a solution of (Z)-tert-butyl4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidine-1-carboxylate(47 mg, 0.10 mmol) in CH₂Cl₂ (0.6 mL) at 0° C. was added TFA (0.04 mL,0.51 mmol) dropwise. The mixture was stirred at 0° C. for 30 minutes andat room temperature overnight. The mixture was concentrated to drynessin vacuo, cooled to 0° C., basified with 1 N NaOH and then extractedthree times with EtOAc. The extracts were washed with brine, dried overMgSO₄ and concentrated in vacuo to give(Z)-5-Cyclopropyl-3-(2,6-dichlorophenyl)-4-(2-(piperidin-4-yl)vinyl)isoxazole(36.8 mg, 1.0 mmol, 100% yield) as an of off-white solid. The productwas used without further purification. ¹H NMR (400 MHz, CDCl₃) δ7.42-7.38 (m, 2H), 7.35-7.29 (m, 1H), 5.94 (d, J=11.0 Hz, 1H), 5.50 (t,J=10.7 Hz, 1H), 3.15 (br d, J=12.8 Hz, 2H), 2.63 (td, J=12.5, 2.5 Hz,2H), 2.40-2.25 (m, 1H), 1.96 (tt, J=8.4, 5.1 Hz, 1H), 1.51-1.36 (m, 2H),1.33-1.21 (m, 5H), 1.13-1.04 (m, 2H).

Example 3.(Z)-6-(4-(2-(5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)nicotinicacid

The title compound was prepared as described in General Method A1 forthe preparation of Example 1 with the replacement of(E)-5-Cyclopropyl-3-(2,6-dichlorophenyl)-4-(2-(piperidin-4-yl)vinyl)isoxazolewith(Z)-5-Cyclopropyl-3-(2,6-dichlorophenyl)-4-(2-(piperidin-4-yl)vinyl)isoxazolein step 10. MS (ESI) m/z: 484.3 [M+H]+; ¹H NMR (500 MHz, DMSO-d₆) δ 8.57(d, J=2.4 Hz, 1H), 7.88 (dd, J=2.4, 9.2 Hz, 1H), 7.65 (d, J=8.1 Hz, 2H),7.57 (dd, J=7.3, 9.0 Hz, 1H), 6.80 (d, J=9.2 Hz, 1H), 5.87 (d, J=11.1Hz, 1H), 5.55 (t, J=10.8 Hz, 1H), 4.34 (d, J=13.3 Hz, 2H), 2.76 (q,J=9.3, 11.8 Hz, 2H), 2.34 (d, J=9.9 Hz, 1H), 2.09 (td, J=5.6, 9.9, 11.2Hz, 1H), 1.28-1.00 (m, 8H); HLE GAL-FXR EC₅₀=107 nM.

Example 4(E)-2-(4-(1-(5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)prop-1-en-2-yl)piperidin-1-yl)-4-fluorobenzo[d]thiazole-6-carboxylicacid

Step 1. tert-Butyl(E)-4-(1-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)prop-1-en-2-yl)piperidine-1-carboxylate

To a solution of diethyl((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl) methyl)phosphonate(0.21 g, 0.51 mmol, synthesis described in General Method A) in toluene(1.3 mL), was added tert-butyl 4-acetylpiperidine-1-carboxylate (0.17 g,0.76 mmol), KOtBu (0.11 g, 1.0 mmol), and 18-crown-6 (0.27 g, 1.0 mmol).The reaction mixture was heated for 2 h at 50° C. and was diluted withH₂O and extracted with EtOAc. The EtOAc layer was concentrated in vacuoto dryness. The resulting residue was purified by flash chromatographyon SiO₂ (0-15% EtOAc/hexanes, Isco 40 g column) to give a mixture of Eand Z isomers; tert-butyl(E)-4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)-4-methylpiperidine-1-carboxylateand tert-butyl(Z)-4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)-4-methylpiperidine-1-carboxylate(0.10 g) as a white solid. The E and Z isomers were separated bypreparative SFC (Column: Chiralpak IC, 4.6×250 mm, 5 μM; Mobile Phase15% MeOH/85% CO₂, Flow: 2.0 mL/min, 150 Bar, 40° C.) to yield tert-butyl(E)-4-(1-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)prop-1-en-2-yl)piperidine-1-carboxylate(75 mg, 0.16 mmol, 31% yield) upon concentration in vacuo. ¹H NMR (500MHz, CDCl₃) δ 7.39 (s, 1H), 7.38 (s, 1H), 7.33-7.29 (m, 1H), 5.66 (s,1H), 4.14 (br d, J=6.6 Hz, 2H), 2.66 (br s, 2H), 2.12-2.02 (m, 1H), 1.88(tt, J=8.5, 5.2 Hz, 1H), 1.62-1.59 (m, 2H), 1.58 (d, J=1.1 Hz, 3H), 1.46(s, 9H), 1.41-1.31 (m, 2H), 1.24-1.20 (m, 2H), 1.11-1.05 (m, 2H).

Step 2.(E)-5-Cyclopropyl-3-(2,6-dichlorophenyl)-4-(2-(piperidin-4-yl)prop-1-en-1-yl)isoxazole

To a 1 dram vial was added tert-butyl(E)-4-(1-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)prop-1-en-2-yl)piperidine-1-carboxylate(0.16 g, 0.34 mmol), dichloromethane (0.34 mL) and TFA (0.13 mL, 1.7mmol). After 30 minutes the reaction mixture was cooled to 0° C. andbasified with 1N NaOH until ˜pH 8-9. More dichloromethane was added andthe mixture was washed with H₂O. The aqueous layer was extracted threetimes with dichloromethane, and the combined organic layers where driedover Na₂SO₄, filtered, and concentrated in vacuo to give(E)-5-cyclopropyl-3-(2,6-dichlorophenyl)-4-(2-(piperidin-4-yl)prop-1-en-1-yl)isoxazole(0.13 g, 0.34 mmol, 99% yield) as an off-white foam.

Example 4.(E)-2-(4-(1-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)prop-1-en-2-yl)piperidin-1-yl)-4-fluorobenzo[d]thiazole-6-carboxylicacid

The title compound was prepared as described in General Method A1 forthe preparation of Example 1 with the replacement of(E)-5-cyclopropyl-3-(2,6-dichlorophenyl)-4-(2-(piperidin-4-yl)vinyl)isoxazoleand methyl 6-fluoronicotinate with(E)-5-cyclopropyl-3-(2,6-dichlorophenyl)-4-(2-(piperidin-4-yl)prop-1-en-1-yl)isoxazoleand ethyl 2-bromo-4-fluorobenzo[d]thiazole-6-carboxylate. MS (ESI) m/z:572.3 [M+H]+; ¹H NMR (500 MHz, DMSO-d₆) δ 8.24-8.06 (m, 1H), 7.61-7.59(m, 1H), 7.59-7.56 (m, 2H), 7.55-7.50 (m, 1H), 5.67 (s, 1H), 4.08 (br d,J=10.6 Hz, 2H), 3.23 (br s, 2H), 2.35-2.26 (m, 1H), 2.04-1.95 (m, 1H),1.70 (br d, J=12.6 Hz, 2H), 1.54 (s, 3H), 1.51-1.41 (m, 2H), 1.15-1.09(m, 2H), 1.07-1.02 (m, 2H); HLE GAL-FXR EC₅₀=2055 nM.

Example 5(E)-6-(4-(1-(5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)prop-1-en-2-yl)piperidin-1-yl)quinoline-2-carboxylicacid

The title compound was prepared as described in General Method A2 forthe preparation of Example 2 with the replacement of(E)-5-cyclopropyl-3-(2,6-dichlorophenyl)-4-(2-(piperidin-4-yl)vinyl)isoxazoleand methyl 6-bromo-1-methyl-1H-indole-3-carboxylate with(E)-5-cyclopropyl-3-(2,6-dichlorophenyl)-4-(2-(piperidin-4-yl)prop-1-en-1-yl)isoxazoleand methyl 6-bromoquinoline-2-carboxylate. MS (ESI) m/z: 548.4 [M+H]+;¹H NMR (500 MHz, DMSO-d₆) δ 7.66-7.48 (m, 5H), 7.25-6.93 (m, 3H),5.62-5.58 (m, 1H), 4.36-4.14 (m, 2H), 4.03-3.85 (m, 2H), 2.56 (br s,2H), 2.19-2.11 (m, 1H), 2.00-1.96 (m, 1H), 1.59-1.54 (m, 2H), 1.50 (brs, 3H), 1.11 (br d, J=5.5 Hz, 2H), 1.03 (br d, J=1.3 Hz, 2H); HLEGAL-FXR EC₅₀=1250 nM.

Example 6(E)-2-(4-(2-(5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)-4-methylpiperidin-1-yl)-4-fluorobenzo[d]thiazole-6-carboxylicacid

Step 1. tert-Butyl(E)-4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)-4-methylpiperidine-1-carboxylate

The title compound was prepared as described for the preparation oftert-butyl(E)-4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidine-1-carboxylate(General Method A, step 8) with replacement of tert-butyl4-formylpiperidine-1-carboxylate with tert-butyl4-formyl-4-methylpiperidine-1-carboxylate. ¹H NMR (500 MHz, CDCl₃) δ7.48-7.42 (m, 2H), 7.40-7.35 (m, 1H), 6.05 (d, J=16.8 Hz, 1H), 5.44 (d,J=16.5 Hz, 1H), 3.76-3.60 (m, 1H), 3.49 (br d, J=11.6 Hz, 2H), 3.22-3.10(m, 1H), 3.10-2.99 (m, 2H), 2.17-2.06 (m, 1H), 1.99-1.87 (m, 1H), 1.47(s, 9H), 1.42 (br d, J=4.1 Hz, 2H), 1.37-1.30 (m, 3H), 1.30-1.24 (m,2H), 1.21-1.13 (m, 2H).

Step 2.(E)-5-Cyclopropyl-3-(2,6-dichlorophenyl)-4-(2-(4-methylpiperidin-4-yl)vinyl)isoxazole

To a 10 mL flask was added (E)-tert-butyl4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)-4-methylpiperidine-1-carboxylate(0.13 g, 0.27 mmol), dichloromethane (0.27 mL) and TFA (0.10 mL, 1.3mmol). The reaction mixture was stirred at room temperature for 30minutes and then more TFA (0.10 mL, 1.3 mmol) was added. After 20minutes 1.0 M NaOH added until pH>7. The mixture was diluted withdichloromethane and washed with H₂O. The dichloromethane layer waswashed with brine, dried over Na₂SO₄, filtered, and concentrated invacuo to give(E)-5-cyclopropyl-3-(2,6-dichlorophenyl)-4-(2-(4-methylpiperidin-4-yl)vinyl)isoxazole(0.10 g, 0.26 mmol, 98% yield) as a colorless oil. The product was usedin subsequent steps without further purification or characterization.

Example 6.(E)-2-(4-(2-(5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)-4-methylpiperidin-1-yl)-4-fluorobenzo[d]thiazole-6-carboxylicacid

The title compound was prepared as described in General Method A1 forthe preparation of Example 1 with the replacement of(E)-5-cyclopropyl-3-(2,6-dichlorophenyl)-4-(2-(piperidin-4-yl)vinyl)isoxazoleand methyl 6-fluoronicotinate with(E)-5-cyclopropyl-3-(2,6-dichlorophenyl)-4-(2-(4-methylpiperidin-4-yl)vinyl)isoxazoleand ethyl 2-bromo-4-fluorobenzo[d]thiazole-6-carboxylate. MS (ESI) m/z:572.0 [M+H]+; ¹H NMR (500 MHz, DMSO-d₆) δ 8.19 (br s, 1H), 7.65 (s, 1H),7.64 (s, 1H), 7.61-7.52 (m, 2H), 6.27 (d, J=16.8 Hz, 1H), 5.32 (d,J=16.8 Hz, 1H), 3.74-3.56 (m, 1H), 3.29-3.20 (m, 1H), 3.16 (s, 1H),2.45-2.35 (m, 1H), 1.56-1.50 (m, 2H), 1.49-1.41 (m, 2H), 1.22 (s, 1H),1.19-1.14 (m, 2H), 1.09 (br d, J=3.1 Hz, 2H), 0.97 (s, 3H); HLE GAL-FXREC₅₀=536 nM.

Example 7(E)-6-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)-4-methylpiperidin-1-yl)quinoline-2-carboxylicacid

The title compound was prepared as described in General Method A2 forthe preparation of Example 2 with the replacement of(E)-5-cyclopropyl-3-(2,6-dichlorophenyl)-4-(2-(piperidin-4-yl)vinyl)isoxazoleand methyl 6-bromo-1-methyl-1H-indole-3-carboxylate with(E)-5-cyclopropyl-3-(2,6-dichlorophenyl)-4-(2-(4-methylpiperidin-4-yl)vinyl)isoxazoleand methyl 6-bromoquinoline-2-carboxylate. MS (ESI) m/z: 548.0 [M+H]+;¹H NMR (500 MHz, DMSO-d₆) δ 8.24 (br d, J=8.5 Hz, 1H), 7.97 (d, J=8.5Hz, 1H), 7.93 (br d, J=9.5 Hz, 1H), 7.65 (br d, J=7.3 Hz, 1H), 7.61 (s,1H), 7.59 (s, 1H), 7.53-7.45 (m, 1H), 7.15 (br d, J=2.1 Hz, 1H),6.30-6.29 (m, 1H), 6.26 (d, J=16.5 Hz, 1H), 5.38 (d, J=16.8 Hz, 1H),2.94 (br t, J=8.9 Hz, 2H), 2.44-2.34 (m, 1H), 1.58-1.41 (m, 4H), 1.23(s, 2H), 1.16 (br d, J=7.9 Hz, 2H), 1.09 (br d, J=2.4 Hz, 2H), 0.99 (s,3H); HLE GAL-FXR EC₅₀=227 nM.

Example 8(E)-2-(6-(2-(5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-4-fluorobenzo[d]thiazole-6-carboxylicacid

Step 1. tert-Butyl(E)-6-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of diethyl((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methyl)phosphonate(0.46 g, 1.14 mmol, synthesis described in General Method A) andtert-butyl 6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.29 g, 1.4mmol) in THF (7 mL) at 40° C., was added KOtBu (1.0 M in THF, 1.4 mL,1.4 mmol). The reaction mixture was quenched with 2 mL of saturatedaqueous NH₄Cl, and extracted with EtOAc (2×20 mL). The combined EtOAclayers were concentrated in vacuo giving a yellow oil. The residue waspurified by preparative HPLC (Phenomenex Axia Luna C18 5μ30×100 mmcolumn, 10 minute gradient from 5 to 100% B in A, A=10:90:0.1MeCN:H₂O:TFA, B=90:10:0.1 MeCN:H₂O:TFA). The product containingfractions were combined, and concentrated in vacuo to give tert-butyl(E)-6-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(0.40 g, 0.88 mmol, 77% yield) as a foam. ¹H NMR (400 MHz, CDCl₃) δ7.46-7.39 (m, 2H), 7.39-7.32 (m, 1H), 6.04 (d, J=16.1 Hz, 1H), 5.12 (dd,J=16.0, 8.7 Hz, 1H), 3.70-3.48 (m, 2H), 3.44-3.26 (m, 2H), 2.08 (tt,J=8.4, 5.1 Hz, 1H), 1.43 (s, 11H), 1.31-1.20 (m, 3H), 1.17-1.05 (m, 2H).

Step 2.(E)-4-(2-(3-Azabicyclo[3.1.0]hexan-6-yl)vinyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole

To a 1 dram vial was added tert-butyl(E)-6-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(85.1 mg, 0.18 mmol), dichloromethane (184 μL) and TFA (355 μL, 4.6mmol), and the mixture was stirred for 30 minutes. The reaction mixturewas neutralized with 1.0 N NaOH, diluted with dichloromethane and washedwith H₂O. The dichloromethane layer was dried over Na₂SO₄, filtered, andconcentrated in vacuo giving(E)-4-(2-(3-azabicyclo[3.1.0]hexan-6-yl)vinyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole(66.5 mg, 0.18 mmol, 100% yield) as a white foam. The product was usedwithout further purification or characterization. MS (ESI) m/z: 361.0[M+H]⁺.

Example 8.(E)-2-(6-(2-(5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-4-fluorobenzo[d]thiazole-6-carboxylicacid

The title compound was prepared as described in General Method A1 forthe preparation of Example 1 with the replacement of(E)-5-cyclopropyl-3-(2,6-dichlorophenyl)-4-(2-(piperidin-4-yl)vinyl)isoxazoleand methyl 6-fluoronicotinate with(E)-4-(2-(3-azabicyclo[3.1.0]hexan-6-yl)vinyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazoleand ethyl 2-bromo-4-fluorobenzo[d]thiazole-6-carboxylate. MS (ESI) m/z:556.2 [M+H]+; ¹H NMR (500 MHz, DMSO-d₆) δ 8.21 (d, J=1.4 Hz, 1H), 7.66(d, J=1.4 Hz, 1H), 7.65 (s, 1H), 7.60 (d, J=6.9 Hz, 1H), 7.58 (d, J=7.2Hz, 1H), 6.13 (d, J=16.0 Hz, 1H), 5.19 (dd, J=16.2, 8.8 Hz, 1H),3.80-3.63 (m, 4H), 2.38-2.30 (m, 1H), 1.75 (br s, 2H), 1.47-1.37 (m,1H), 1.20-1.12 (m, 2H), 1.11-1.03 (m, 2H); HLE GAL-FXR EC₅₀=120 nM.

Example 9(E)-6-(6-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-2-carboxylicacid

The title compound was prepared as described in General Method A2 forthe preparation of Example 2 with the replacement of(E)-5-cyclopropyl-3-(2,6-dichlorophenyl)-4-(2-(piperidin-4-yl)vinyl)isoxazoleand methyl 6-bromo-1-methyl-1H-indole-3-carboxylate with(E)-4-(2-(3-azabicyclo[3.1.0]hexan-6-yl)vinyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazoleand methyl 6-bromoquinoline-2-carboxylate. MS (ESI) m/z: 531.9 [M+H]+;¹H NMR (500 MHz, DMSO-d₆) δ 8.13 (d, J=8.5 Hz, 1H), 7.92 (d, J=3.6 Hz,1H), 7.90 (d, J=4.1 Hz, 1H), 7.67 (d, J=1.4 Hz, 1H), 7.66 (s, 1H),7.62-7.57 (m, 1H), 7.32 (dd, J=9.4, 2.5 Hz, 1H), 6.78 (d, J=2.5 Hz, 1H),6.15 (d, J=16.2 Hz, 1H), 5.16 (dd, J=16.1, 8.9 Hz, 1H), 3.69 (d, J=9.9Hz, 2H), 3.58-3.53 (m, 2H), 3.16 (br d, J=5.5 Hz, 2H), 2.38-2.32 (m,1H), 1.47-1.35 (m, 1H), 1.22-1.13 (m, 2H), 1.11-1.05 (m, 2H); HLEGAL-FXR EC₅₀=39 nM.

General Method B Example 10(E)-2-(4-(2-(4-Cyclopropyl-1-(2,6-dichlorophenyl)-1H-1,2,3-triazol-5-yl)vinyl)piperidin-1-yl)-4-fluorobenzo[d]thiazole-6-carboxylicacid

Step 1. 2-Azido-1,3-dichlorobenzene

To a solution of 2,6-dichloroaniline (0.96 g, 5.9 mmol) in TFA (10 mL)and water (2 mL) at 0° C. was added sodium nitrite (0.41 g, 5.9 mmol)over the space of 30 minutes. Sodium azide (0.98 g, 15.0 mmol) dissolvedin minimal water was then added gradually. The reaction mixture wasstirred at 0° C. for 10 minutes, and allowed to warm to roomtemperature. After 2 h, the reaction was quenched with water, andextracted with EtOAc. The organic layer was concentrated in vacuo andthe residue was purified by flash chromatography on SiO₂ (0-20%EtOAc/hexanes) to afford 2-azido-1,3-dichlorobenzene (1.1 g, 5.7 mmol,97% yield) as an oil. ¹H NMR (500 MHz, CDCl₃) δ 7.30 (d, J=8.25 Hz, 2H),7.05 (t, J=8.12 Hz, 1H)

Step 2.(4-Cyclopropyl-1-(2,6-dichlorophenyl)-1H-1,2,3-triazol-5-yl)methanol

A mixture of 2-azido-1,3-dichlorobenzene (3.5 g, 18.6 mmol) and3-cyclopropylprop-2-yn-1-ol (1.8 g, 18.6 mmol) in toluene (12.4 mL) wassealed and heated at 110° C. over the weekend. The crude reactionmixture was purified by flash chromatography on SiO₂ (0-100%EtOAc/hexanes) to afford(4-cyclopropyl-1-(2,6-dichlorophenyl)-1H-1,2,3-triazol-5-yl)methanol(1.2 g, 4.1 mmol, 22% yield) as a tan solid. ¹H NMR (500 MHz, CDCl₃) δ7.49-7.53 (m, 2H), 7.42-7.47 (m, 1H), 4.63 (s, 2H), 1.96-1.99 (m, 1H),1.10-1.16 (m, 2H), 0.99-1.04 (m, 2H).

Step 3.5-(Bromomethyl)-4-cyclopropyl-1-(2,6-dichlorophenyl)-1H-1,2,3-triazole

To a solution of(4-cyclopropyl-1-(2,6-dichlorophenyl)-1H-1,2,3-triazol-5-yl)methanol(0.33 g, 1.2 mmol) in dichloromethane (4.6 mL) was addedtriphenylphosphine (0.79 g, 3.0 mmol). After 15 minutes, CBr₄ (1.0 g,3.0 mmol) was added portionwise. The resulting mixture was stirred atroom temperature for 1 h and the crude reaction mixture was purified byflash chromatography on SiO₂ (0-20% EtOAc/hexanes) to afford5-(bromomethyl)-4-cyclopropyl-1-(2,6-dichlorophenyl)-1H-1,2,3-triazole(426 mg, 1.154 mmol, 99% yield) as a tan foam. ¹H NMR (500 MHz, CDCl₃) δ7.52-7.58 (m, 2H), 7.47-7.51 (m, 1H), 4.38 (s, 2H), 1.87-1.98 (m, 1H),1.18 (dd, J=2.06, 4.81 Hz, 2H), 1.02-1.12 (m, 2H).

Step 4. Diethyl((4-cyclopropyl-1-(2,6-dichlorophenyl)-1H-1,2,3-triazol-5-yl)methyl)phosphonate

A mixture of5-(bromomethyl)-4-cyclopropyl-1-(2,6-dichlorophenyl)-1H-1,2,3-triazole(1.5 g, 4.3 mmol) and triethyl phosphite (1.3 g, 7.8 mmol) in dioxane(1.4 mL) was heated with stirring in a sealed tube at 120° C. overnight.The reaction mixture was loaded directly onto to a SiO₂ gel column forpurification by flash chromatography (0-80% EtOAc/hexanes) to afforddiethyl((4-cyclopropyl-1-(2,6-dichlorophenyl)-1H-1,2,3-triazol-5-yl)methyl)phosphonate(1.81 g, 4.30 mmol, 99% yield) as an off-white solid. ¹H NMR (400 MHz,CDCl₃) δ 7.46-7.52 (m, 2H), 7.39-7.46 (m, 1H), 3.98 (ddd, J=7.26, 8.47,14.64 Hz, 4H), 3.10-3.22 (m, 2H), 1.90-1.99 (m, 1H), 1.21 (t, J=7.04 Hz,6H), 1.07-1.15 (m, 2H), 1.00 (dd, J=2.31, 8.25 Hz, 2H).

Step 5. tert-Butyl(E)-4-(2-(4-cyclopropyl-1-(2,6-dichlorophenyl)-1H-1,2,3-triazol-5-yl)vinyl)piperidine-1-carboxylate

To a solution of diethyl((4-cyclopropyl-1-(2,6-dichlorophenyl)-1H-1,2,3-triazol-5-yl)methyl)phosphonate(0.66 g, 1.6 mmol) in THF (12.0 mL) at −78° C. under nitrogenatmosphere, LiHMDS (1.0 M in THF) (3.1 mL, 3.1 mmol) was added dropwise.The mixture was stirred for 30 minutes and a solution of tert-butyl4-formylpiperidine-1-carboxylate (0.33 g, 1.6 mmol) in THF (2.0 mL) wasadded. The reaction was allowed to warm up to room temperature. Afterthree h the reaction was quenched with 0.3 mL of MeOH, and filteredthrough a pad of SiO₂ gel and concentrated in vacuo to an oil. The oilwas purified by flash chromatography on SiO₂ (0-15% EtOAc/hexanes IscoSiO₂ column) to give tert-butyl(E)-4-(2-(4-cyclopropyl-1-(2,6-dichlorophenyl)-1H-1,2,3-triazol-5-yl)vinyl)piperidine-1-carboxylate(0.35 g, 0.75 mmol, 48% yield) as a solid. ¹H NMR (400 MHz, CDCl₃) δ7.44-7.54 (m, 3H), 5.97-6.08 (m, 2H), 4.07 (br d, J=10.34 Hz, 2H), 2.74(br s, 2H), 2.22 (br d, J=5.94 Hz, 1H), 1.88-1.97 (m, 1H), 1.65 (br dd,J=1.98, 12.98 Hz, 2H), 1.46 (s, 9H), 1.22-1.31 (m, 2H), 1.14 (dd,J=1.76, 5.28 Hz, 2H), 1.04 (dd, J=2.31, 8.25 Hz, 2H).

Step 6.(E)-4-(2-(4-Cyclopropyl-1-(2,6-dichlorophenyl)-1H-1,2,3-triazol-5-yl)vinyl)piperidine

To a solution of (E)-tert-butyl4-(2-(4-cyclopropyl-1-(2,6-dichlorophenyl)-1H-1,2,3-triazol-5-yl)vinyl)piperidine-1-carboxylate(46 mg, 0.10 mmol) in dichloromethane (0.5 mL) was added HCl (4 M indioxane, 0.30 mL, 1.2 mmol). The reaction was stirred at 25° C. for 90minutes and was concentrated in vacuo to afford(E)-4-(2-(4-cyclopropyl-1-(2,6-dichlorophenyl)-1H-1,2,3-triazol-5-yl)vinyl)piperidine,HCl (39 mg, 0.10 mmol, 100% yield) as an off-white solid. The productwas used without further purification or characterization.

Example 10.(E)-2-(4-(2-(4-Cyclopropyl-1-(2,6-dichlorophenyl)-1H-1,2,3-triazol-5-yl)vinyl)piperidin-1-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid

The title compound was prepared as described in General Method A1 forthe preparation of Example 1 with the replacement of(E)-5-cyclopropyl-3-(2,6-dichlorophenyl)-4-(2-(piperidin-4-yl)vinyl)isoxazoleand methyl 6-fluoronicotinate with(E)-4-(2-(4-Cyclopropyl-1-(2,6-dichlorophenyl)-1H-1,2,3-triazol-5-yl)vinyl)piperidineand ethyl 2-bromo-4-fluorobenzo[d]thiazole-6-carboxylate. MS (ESI) m/z:558.2 [M+H]+; ¹H NMR (500 MHz, DMSO-d₆) δ 8.15 (s, 1H), 7.74-7.79 (m,2H), 7.69 (br d, J=7.63 Hz, 1H), 7.57 (br d, J=11.29 Hz, 1H), 6.12 (d,J=16.17 Hz, 1H), 5.96-6.03 (m, 1H), 4.00 (br d, J=10.07 Hz, 1H), 3.22(br t, J=11.90 Hz, 2H), 2.04 (br s, 1H), 1.71 (br d, J=11.29 Hz, 2H),1.24-1.37 (m, 2H), 1.01 (br d, J=5.80 Hz, 2H), 0.86-0.93 (m, 2H); HLEGAL-FXR EC₅₀=64 nM.

General Method C Example 11(E)-6-(4-(2-(4-Cyclopropyl-1-(2,6-dichlorophenyl)-1H-pyrazol-5-yl)vinyl)piperidin-1-yl)nicotinic acid

Step 1. Ethyl 3-cyclopropyl-4-(dimethylamino)-2-oxobut-3-enoate

A mixture of ethyl 3-cyclopropyl-2-oxopropanoate (0.50 g, 3.2 mmol) and1,1-dimethoxy-N,N-dimethylmethanamine (0.68 mL, 5.1 mmol) in THF (1.75mL) was heated in a sealed tube at 80° C. for 2 h. The reaction mixturewas concentrated to dryness in vacuo and the residue was purified byflash chromatography on SiO₂ (0-80% EtOAc/hexanes) to afford ethyl3-cyclopropyl-4-(dimethylamino)-2-oxobut-3-enoate (0.52 g, 2.5 mmol, 77%yield) as an oil. ¹H NMR (400 MHz, CDCl₃) δ 7.21-7.47 (m, 1H), 4.27 (q,J=7.04 Hz, 2H), 3.23 (br s, 6H), 1.48 (br t, J=7.04 Hz, 1H), 1.33 (t,J=7.15 Hz, 3H), 0.79 (q, J=5.80 Hz, 2H), 0.39-0.47 (m, 2H).

Step 2. Ethyl4-cyclopropyl-1-(2,6-dichlorophenyl)-1H-pyrazole-5-carboxylate

To a solution of ethyl 3-cyclopropyl-4-(dimethylamino)-2-oxobut-3-enoate(0.40 g, 1.9 mmol) in EtOH (4.0 mL) was added(2,6-dichlorophenyl)hydrazine (0.34 g, 1.9 mmol). The reaction flask wassealed and heated with stirring at 90° C. for 3 h. The reaction mixturewas concentrated in vacuo, and the residue was purified by flashchromatography on SiO₂ (0-30% EtOAc/hexanes) to afford ethyl4-cyclopropyl-1-(2,6-dichlorophenyl)-1H-pyrazole-5-carboxylate (0.40 g,1.2 mmol, 63% yield) as an oil which solidified upon standing. ¹H NMR(400 MHz, CDCl₃) δ 7.20-7.30 (m, 3H), 7.13-7.19 (m, 1H), 4.03 (q, J=7.04Hz, 2H), 2.25 (tt, J=5.14, 8.50 Hz, 1H), 0.96 (t, J=7.15 Hz, 3H), 0.88(dd, J=1.87, 8.47 Hz, 2H), 0.57 (dd, J=1.76, 5.28 Hz, 2H).

Step 3. (4-Cyclopropyl-1-(2,6-dichlorophenyl)-1H-pyrazol-5-yl)methanol

To a solution of ethyl4-cyclopropyl-1-(2,6-dichlorophenyl)-1H-pyrazole-5-carboxylate (0.32 g,0.97 mmol) in THF (3.9 mL) at 0° C. was added diisobutyl aluminumhydride (1.0 M in toluene) (3.9 mL, 3.9 mmol) dropwise over 15 minutes.The reaction mixture was then allowed to warm to room temperature. After1 h the mixture was diluted with EtOAc, washed with 0.1M HCl, brine,dried over MgSO₄, filtered, and concentrated in vacuo to afford(4-cyclopropyl-1-(2,6-dichlorophenyl)-1H-pyrazol-5-yl)methanol (243 mg,0.86 mmol, 88% yield) as a tan solid. The product was used withoutfurther purification. ¹H NMR (500 MHz, CDCl₃) δ 7.42-7.49 (m, 3H),7.35-7.42 (m, 1H), 4.54 (br s, 2H), 0.95 (br d, J=7.98 Hz, 2H),0.62-0.74 (m, 2H).

Step 4. 5-(Bromomethyl)-4-cyclopropyl-1-(2,6-dichlorophenyl)-1H-pyrazole

To a solution of(4-cyclopropyl-1-(2,6-dichlorophenyl)-1H-pyrazol-5-yl)methanol (0.15 g,0.52 mmol) in dichloromethane (2.1 mL) was added triphenylphosphine(0.34 g, 1.3 mmol). After stirring the mixture for 15 minutes CBr₄ (0.43g, 1.3 mmol) was added portion wise, and the resulting mixture wasstirred at room temperature for 90 minutes. The crude reaction mixturewas directly purified by flash chromatography on SiO₂ (0-20%EtOAc/hexanes) to afford5-(bromomethyl)-4-cyclopropyl-1-(2,6-dichlorophenyl)-1H-pyrazole (0.15g, 0.44 mmol, 85% yield) as a tan solid. ¹H NMR (500 MHz, CDCl₃) δ7.44-7.51 (m, 3H), 7.38-7.43 (m, 1H), 4.37 (s, 2H), 1.75 (tt, J=5.05,8.42 Hz, 1H), 0.92-1.03 (m, 2H), 0.66-0.76 (m, 2H).

Step 5. Diethyl((4-cyclopropyl-1-(2,6-dichlorophenyl)-1H-pyrazol-5-yl)methyl)phosphonate

A solution of5-(bromomethyl)-4-cyclopropyl-1-(2,6-dichlorophenyl)-1H-pyrazole (61 mg,0.18 mmol) and triethyl phosphite (0.06 mL, 0.35 mmol) in dioxane (0.1mL) was heated with stirring in a sealed tube at 140° C. overnight. Thereaction mixture was cooled to room temperature and the crude mixturewas directly purified by flash chromatography on SiO₂ (0-80%EtOAc/hexanes) to afford diethyl((4-cyclopropyl-1-(2,6-dichlorophenyl)-1H-pyrazol-5-yl)methyl)phosphonate(64 mg, 0.16 mmol, 90% yield) as a film. ¹H NMR (400 MHz, CDCl₃) δ7.43-7.38 (m, 2H), 7.33-7.26 (m, 1H), 7.10 (s, 1H), 4.10 (t, J=7.3 Hz,4H), 3.41 (s, 1H), 3.35 (s, 1H), 1.89 (s, 1H), 1.28 (t, J=7.0 Hz, 6H),0.94-0.87 (m, 2H), 0.52 (dd, J=5.1, 1.8 Hz, 2H).

Step 6. tert-Butyl(E)-4-(2-(4-cyclopropyl-1-(2,6-dichlorophenyl)-1H-pyrazol-5-yl)vinyl)piperidine-1-carboxylate

To a solution of diethyl((4-cyclopropyl-1-(2,6-dichlorophenyl)-1H-pyrazol-5-yl)methyl)phosphonate(0.11 g, 0.26 mmol) in THF (2.5 mL) at −78° C. was added n-butyllithium(2.5 M in hexanes) (0.12 mL, 0.29 mmol) dropwise. The mixture wasstirred for 15 minutes and a solution of tert-butyl4-formylpiperidine-1-carboxylate (62.3 mg, 0.29 mmol) in THF (0.5 mL)was added. The reaction mixture was allowed to warm to room temperature.After 30 minutes, the reaction was diluted with EtOAc, washed with waterand brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Theresidue was purified by flash chromatography on SiO₂ (0-20%EtOAc/hexanes) to afford tert-butyl(E)-4-(2-(4-cyclopropyl-1-(2,6-dichlorophenyl)-1H-pyrazol-5-yl)vinyl)piperidine-1-carboxylate(56 mg, 0.12 mmol, 46% yield) as an oil containing˜25% of tert-butyl(Z)-4-(2-(4-cyclopropyl-1-(2,6-dichlorophenyl)-1H-pyrazol-5-yl)vinyl)piperidine-1-carboxylate.MS (ESI) m/z: 462.2 [M+H]⁺.

Step 7.(E)-4-(2-(4-Cyclopropyl-1-(2,6-dichlorophenyl)-1H-pyrazol-5-yl)vinyl)piperidine

To a solution of tert-butyl(E)-4-(2-(3-cyclopropyl-1-(2,6-dichlorophenyl)-1H-pyrrol-2-yl)vinyl)piperidine-1-carboxylate(56 mg, 0.12 mmol) in dichloromethane (0.36 mL) was added HCl (4 M indioxane, 0.36 mL, 1.5 mmol). The reaction was stirred at 25° C. for 1 hand was concentrated in vacuo to afford(E)-4-(2-(4-cyclopropyl-1-(2,6-dichlorophenyl)-1H-pyrazol-5-yl)vinyl)piperidine,HCl (50 mg, 0.13 mmol, 100% yield) as a tan solid. The product was usedwithout further purification or characterization. MS (ESI) m/z: 362.1[M+H]⁺.

Example 11.(E)-6-(4-(2-(4-Cyclopropyl-1-(2,6-dichlorophenyl)-1H-pyrazol-5-yl)vinyl)piperidin-1-yl)nicotinicacid

The title compound was prepared as described in General Method A1 forthe preparation of Example 1 with the replacement of(E)-5-cyclopropyl-3-(2,6-dichlorophenyl)-4-(2-(piperidin-4-yl)vinyl)isoxazolewith(E)-4-(2-(4-cyclopropyl-1-(2,6-dichlorophenyl)-1H-pyrazol-5-yl)vinyl)piperidine,HCl. MS (ESI) m/z: 482.8 [M+H]+; ¹H NMR (500 MHz, DMSO-d₆) δ 8.50-8.58(m, 1H), 7.83 (br s, 1H), 7.64 (s, 2H), 7.56 (br d, J=8.24 Hz, 1H), 7.40(s, 1H), 6.77 (br d, J=9.16 Hz, 1H), 5.94-6.03 (m, 1H), 5.90 (br d,J=7.02 Hz, 1H), 4.30 (br d, J=12.51 Hz, 2H), 4.23 (br d, J=7.02 Hz, 1H),2.83-2.94 (m, 2H), 1.72 (br s, 1H), 1.59 (br d, J=12.51 Hz, 2H), 1.12(br d, J=9.46 Hz, 2H), 0.85 (br d, J=6.71 Hz, 2H), 0.54 (br d, J=3.97Hz, 2H); HLE GAL-FXR EC₅₀=148 nM.

General Method D Example 12(E)-2-(4-(2-(1-Cyclopropyl-4-(2,6-dichlorphenyl)-1H-pyrazol-5-yl)vinyl)piperidin-1-yl)-4-fluorobenzo[d]thiazole-6-carboxylicacid

Step 1. 1-Cyclopropyl-4-(2,6-dichlorophenyl)-1H-pyrazole

A mixture of (2,6-dichlorophenyl)boronic acid (1.9 g, 10.1 mmol),4-bromo-1-cyclopropyl-1H-pyrazole (1.7 g, 9.2 mmol), PdCl₂(dppf)-CH₂Cl₂adduct (0.30 g, 0.34 mmol) and Na₂CO₃ (1.9 g, 18.4 mmol) in THF (15 mL)and water (5 mL) was degassed and then heated under microwaveirradiation at 100° C. for 3 h. The reaction mixture was diluted withEtOAc, washed with saturated aqueous NH₄Cl and brine, dried over MgSO₄,filtered, and concentrated in vacuo. The residue was purified by flashchromatography on SiO₂ (0-30% EtOAc/hexanes) to afford1-cyclopropyl-4-(2,6-dichlorophenyl)-1H-pyrazole (1.4 g, 5.5 mmol, 60%yield) as an oil which became solid upon standing. ¹H NMR (500 MHz,CDCl₃) δ 7.63 (s, 2H), 7.35-7.43 (m, 2H), 7.15 (t, J=7.98 Hz, 1H), 3.68(tt, J=3.78, 7.36 Hz, 1H), 1.21 (dt, J=1.10, 3.03 Hz, 2H), 1.07 (dd,J=1.93, 7.15 Hz, 2H).

Step 2. 1-Cyclopropyl-4-(2,6-dichlorophenyl)-1H-pyrazole-5-carbaldehyde

To a −78° C. solution of1-cyclopropyl-4-(2,6-dichlorophenyl)-1H-pyrazole (0.59 g, 2.3 mmol) inTHF (4.6 mL) was added n-butyllithium (2.5 M in hexane, 1.2 mL, 2.9mmol) dropwise. The reaction mixture was stirred for 60 minutes followedby dropwise addition of N,N-dimethylformamide (0.23 mL, 2.9 mmol) in THF(2.3 mL). The reaction was continued at −78° C. for an additional 60minutes and was diluted with EtOAc, washed with saturated aqueous NH₄Cland brine, dried over MgSO₄, filtered, and concentrated in vacuo. Theresidue was purified by flash chromatography on SiO₂ (0-10%EtOAc/hexanes) to afford1-cyclopropyl-4-(2,6-dichlorophenyl)-1H-pyrazole-5-carbaldehyde (0.22 g,0.79 mmol, 34% yield) as an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ9.70 (s, 1H), 7.40-7.49 (m, 3H), 7.25-7.33 (m, 1H), 4.38 (tt, J=3.82,7.51 Hz, 1H), 1.27-1.44 (m, 2H), 1.10-1.21 (m, 2H).

Step 3. (1-Cyclopropyl-4-(2,6-dichlorophenyl)-1H-pyrazol-5-yl)methanol

To a solution of1-cyclopropyl-4-(2,6-dichlorophenyl)-1H-pyrazole-5-carbaldehyde (0.22 g,0.77 mmol) in THF (3.1 mL) at 0° C. was added diisobutyl aluminumhydride (1.0 M in toluene, 1.7 mL, 1.7 mmol) dropwise over 15 minutes.The reaction mixture was allowed to warm to room temperature and after 1h was diluted with EtOAc, washed with 0.1M HCl and brine, dried overMgSO₄, filtered and concentrated in vacuo. The residue was purified byflash chromatography on SiO₂ (0-30% EtOAc/hexanes) to afford(1-cyclopropyl-4-(2,6-dichlorophenyl)-1H-pyrazol-5-yl)methanol (0.20 g,0.71 mmol, 90% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ7.36-7.41 (m, 2H), 7.32 (s, 1H), 7.21 (dd, J=7.59, 8.47 Hz, 1H), 4.60(s, 2H), 3.70 (tt, J=3.85, 7.37 Hz, 1H), 2.22 (br s, 1H), 1.23-1.38 (m,2H).

Step 4. 5-(Bromomethyl)-1-cyclopropyl-4-(2,6-dichlorophenyl)-1H-pyrazole

To a solution of(1-cyclopropyl-4-(2,6-dichlorophenyl)-1H-pyrazol-5-yl)methanol (0.13 g,0.45 mmol) in dichloromethane (1.8 mL) was added triphenylphosphine(0.30 g, 1.1 mmol). The reaction mixture was stirred for 15 minutes,followed by portion wise addition of CBr₄ (0.38 g, 1.1 mmol). Theresulting mixture was stirred at room temperature 2 h and was directlypurified by flash chromatography on SiO₂ (0-20% EtOAc/hexanes) to afford5-(bromomethyl)-1-cyclopropyl-4-(2,6-dichlorophenyl)-1H-pyrazole (0.12g, 0.35 mmol, 77% yield) as an oil. ¹H NMR (400 MHz, CDCl₃) δ 7.36-7.43(m, 3H), 7.22-7.29 (m, 1H), 4.45 (s, 2H), 3.61 (tt, J=3.74, 7.26 Hz,1H), 1.26-1.41 (m, 2H), 1.13-1.22 (m, 2H).

Step 5. Diethyl((1-cyclopropyl-4-(2,6-dichlorophenyl)-1H-pyrazol-5-yl)methyl)phosphonate

A solution of5-(bromomethyl)-1-cyclopropyl-4-(2,6-dichlorophenyl)-1H-pyrazole (121mg, 0.35 mmol) and triethyl phosphite (120 μL, 0.70 mmol) in dioxane(120 μL) was heated with stirring in a sealed tube at 120° C. overnight.The reaction was heated at 140° C. for 4 h, cooled to room temperature,and directly purified by flash chromatography on SiO₂ (0-80%EtOAc/hexanes) to afford diethyl((1-cyclopropyl-4-(2,6-dichlorophenyl)-1H-pyrazol-5-yl)methyl)phosphonate(160 mg, 0.35 mmol, 100% yield) as an oil. ¹H NMR (400 MHz, CDCl₃) δ7.39 (s, 2H), 7.35-7.38 (m, 1H), 7.19 (dd, J=7.70, 8.36 Hz, 1H),3.77-3.98 (m, 4H), 3.65-3.77 (m, 1H), 3.40 (s, 1H), 3.34 (s, 1H), 1.27(td, J=1.71, 3.63 Hz, 2H), 1.12-1.20 (m, 6H), 1.10 (dd, J=2.20, 7.26 Hz,2H).

Step 6. tert-Butyl(E)-4-(2-(1-cyclopropyl-4-(2,6-dichlorophenyl)-1H-pyrazol-5-yl)vinyl)piperidine-1-carboxylate

To a −78° C. solution of diethyl((1-cyclopropyl-4-(2,6-dichlorophenyl)-1H-pyrazol-5-yl)methyl)phosphonate(51 mg, 0.13 mmol) in THF (1.5 mL) under nitrogen atmosphere, LiHMDS(1.0 M in THF, 0.25 mL, 0.25 mmol) was added dropwise. The mixture wasstirred for 30 minutes and a solution of tert-butyl4-formylpiperidine-1-carboxylate (27.0 mg, 0.13 mmol) in THF (0.5 mL)was added. The reaction mixture was allowed to warm up to roomtemperature and after 30 minutes was diluted with EtOAc, washed withsaturated aqueous NH₄Cl and brine, dried over MgSO₄, and concentrated invacuo. The residue was purified by flash chromatography on SiO₂ (0-20%EtOAc/hexanes) to afford tert-butyl(E)-4-(2-(1-cyclopropyl-4-(2,6-dichlorophenyl)-1H-pyrazol-5-yl)vinyl)piperidine-1-carboxylate(40 mg, 0.09 mmol, 68% yield) as a film. ¹H NMR (400 MHz, CDCl₃) δ 7.33(d, J=7.9 Hz, 2H), 7.22 (s, 1H), 7.16 (dd, J=8.5, 7.6 Hz, 1H), 6.38 (dd,J=16.3, 0.7 Hz, 1H), 5.48 (dd, J=16.1, 7.0 Hz, 1H), 3.95 (br s, 3H),3.42 (tt, J=7.3, 3.7 Hz, 1H), 2.95-2.83 (m, 1H), 2.68 (br t, J=12.1 Hz,2H), 2.12 (dtd, J=10.6, 7.1, 3.5 Hz, 1H), 1.92-1.79 (m, 1H), 1.40 (s,9H), 1.28-1.18 (m, 3H), 1.08-0.98 (m, 3H).

Step 7.(E)-4-(2-(1-Cyclopropyl-4-(2,6-dichlorophenyl)-1H-pyrazol-5-yl)vinyl)piperidine

To a solution of tert-butyl(E)-4-(2-(1-cyclopropyl-4-(2,6-dichlorophenyl)-1H-pyrazol-5-yl)vinyl)piperidine-1-carboxylate(40 mg, 0.09 mmol) in dichloromethane (0.25 mL) was added HCl (4 M indioxane, 0.26 mL, 1.0 mmol). The reaction was stirred at roomtemperature for 2 h and was concentrated in vacuo to give(E)-4-(2-(1-cyclopropyl-4-(2,6-dichlorophenyl)-1H-pyrazol-5-yl)vinyl)piperidine.The product was used without further purification or characterization.

Example 12.(E)-2-(4-(2-(1-Cyclopropyl-4-(2,6-dichlorophenyl)-1H-pyrazol-5-yl)vinyl)piperidin-1-yl)-4-fluorobenzo[d]thiazole-6-carboxylicacid

The title compound was prepared as described in General Method A1 forthe preparation of Example 1 with the replacement of(E)-5-cyclopropyl-3-(2,6-dichlorophenyl)-4-(2-(piperidin-4-yl)vinyl)isoxazoleand methyl 6-fluoronicotinate with(E)-4-(2-(1-cyclopropyl-4-(2,6-dichlorophenyl)-1H-pyrazol-5-yl)vinyl)piperidineand ethyl 2-bromo-4-fluorobenzo[d]thiazole-6-carboxylate. MS (ESI) m/z:557.0 [M+H]+; ¹H NMR (500 MHz, DMSO-d₆) δ 8.18 (s, 1H), 7.58 (br d,J=11.60 Hz, 1H), 7.53 (s, 2H), 7.40 (d, J=7.93 Hz, 1H), 7.31 (s, 1H),6.54 (d, J=16.48 Hz, 1H), 5.51 (dd, J=7.02, 16.17 Hz, 1H), 3.99 (br d,J=10.68 Hz, 2H), 3.63-3.73 (m, 1H), 3.26 (br t, J=11.60 Hz, 2H), 2.41(br d, J=7.63 Hz, 1H), 1.72 (br d, J=11.60 Hz, 2H), 1.26 (br s, 2H),1.07 (br s, 2H), 0.99 (d, J=6.41 Hz, 2H); HLE GAL-FXR EC₅₀=226 nM.

General Method E Example 56(E)-4-(2-(1-(4-(1H-Tetrazol-5-yl)phenyl)piperidin-4-yl)vinyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole

A mixture of(E)-4-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)benzonitrile(33 mg, 0.071 mmol, Example 50), ammonium acetate (6.6 mg, 0.085 mmol)and sodium azide (5.5 mg, 0.085 mmol) in DMF (0.47 mL) in a sealed tubewas heated at 120° C. for 20 h. The crude material was purified viapreparative LC/MS with the following conditions: Column: XBridge C18,19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with10-mM ammonium acetate; Gradient: 10-80% B over 19 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and dried via centrifugal evaporation togive(E)-4-(2-(1-(4-(1H-tetrazol-5-yl)phenyl)piperidin-4-yl)vinyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole(2.7 mg, 0.005 mmol, 7% yield). MS (ESI) m/z: 507.3 [M+H]⁺; ¹H NMR (500MHz, DMSO-d₆) δ 7.82 (d, J=8.85 Hz, 2H), 7.62-7.67 (m, 2H), 7.54-7.60(m, 1H), 7.03 (br d, J=8.85 Hz, 2H), 6.17 (d, J=16.48 Hz, 1H), 5.32 (dd,J=6.87, 16.33 Hz, 1H), 3.74 (br d, J=13.12 Hz, 2H), 2.81 (br t, J=11.44Hz, 2H), 2.28-2.41 (m, 1H), 2.23 (br s, 1H), 1.62 (br d, J=11.90 Hz,2H), 1.12-1.24 (m, 4H), 1.03-1.11 (m, 2H); HLE GAL-FXR EC₅₀=3 nM.

General Method F Example 70(E)-4-(6-(2-(5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)benzamide

Step 1.(E)-4-(6-(2-(5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)benzonitrile

A slurry of(E)-4-(2-(3-azabicyclo[3.1.0]hexan-6-yl)vinyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole(30 mg, 0.083 mmol), 4-bromobenzonitrile (35 mg, 0.19 mmol) and Cs₂CO₃(75 mg, 0.23 mmol) in dioxane (0.9 mL) was degassed by bubbling nitrogenthrough the mixture for 5 minutes.Chloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(RuPhos-Pd-G2) (7 mg, 9.0 μmol) was then added and the reaction vesselwas sealed and heated to 100° C. for 6 h. The reaction mixture wasfiltered through a pad of Celite, washed with dichloromethane (3 mL).The filtrate was concentrated in vacuo to dryness and purified by flashchromatography on SiO₂ (0-50% EtOAc/hexanes) to afford(E)-4-(6-(2-(5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)benzonitrile(30 mg 89% yield) as a foam. MS (ESI) m/z: 461.9 [M+H]⁺; ¹H NMR (400MHz, CDCl₃) δ 7.48-7.45 (m, 2H), 7.45-7.42 (m, 2H), 7.37 (dd, J=9.2, 6.8Hz, 1H), 6.56-6.41 (m, 2H), 6.08 (d, J=16.0 Hz, 1H), 5.17 (dd, J=16.0,8.7 Hz, 1H), 3.59 (d, J=9.7 Hz, 2H), 3.39 (ddd, J=9.7, 3.0, 1.4 Hz, 2H),2.15-2.01 (m, 2H), 1.68 (td, J=3.1, 1.3 Hz, 2H), 1.36 (dt, J=8.7, 3.3Hz, 1H), 1.32-1.04 (m, 4H).

Example 70.(E)-4-(6-(2-(5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)benzamide

A solution of(E)-4-(6-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)benzonitrile(34 mg, 0.074 mmol), hydroxylamine hydrochloride (6.6 mg, 0.096 mmol)and Na₂CO₃ (8.0 mg, 0.096 mmol) in ethanol (0.7 mL) and water (0.1 mL)was heated at 80° C. in a sealed vial. After 3 h hydroxylaminehydrochloride (14 mg), Na₂CO₃ (17 mg) and ethanol (0.3 mL) were added.The reaction mixture was heated at 80° C. for 20 h. The solvent wasevaporated, the reaction mixture was diluted with water (2 mL) and,extracted with EtOAc (2×8 mL). The combined organic layers wereconcentrated in vacuo to dryness and the residue was purified by flashchromatography on SiO₂ (0-80% EtOAc/hexanes). The product was furtherpurified via preparative LC/MS with the following conditions: Column:XBridge C18, 19×200 mm, 5-m particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 36-76% B over20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to give(E)-4-(6-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)benzamide(3.1 mg, 9% yield) as white solid. MS (ESI) m/z: 480.1 [M+H]⁺; ¹H NMR(500 MHz, DMSO-d₆) δ 7.70 (d, J=8.6 Hz, 2H), 7.67-7.62 (m, 2H), 7.59(dd, J=9.2, 6.8 Hz, 1H), 6.50 (d, J=8.6 Hz, 2H), 6.12 (d, J=16.1 Hz,1H), 5.18 (dd, J=16.1, 8.7 Hz, 1H), 3.56 (d, J=9.9 Hz, 2H), 3.20-3.18(two proton signals were lost due to water suppression), 2.32 (td,J=8.5, 4.3 Hz, 1H), 1.71-1.62 (m, 2H), 1.36 (dt, J=8.8, 3.3 Hz, 1H),1.23-1.01 (m, 4H); HLE GAL-FXR EC₅₀=377 nM.

General Method G Example 71(E)-4-(6-(2-(5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-(methylsulfonyl)benzamide

A mixture of(E)-4-(6-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)benzoicacid (Example 47, 15 mg, 0.031 mmol) and CDI (15.2 mg, 0.093 mmol) inTHF (500 μL) was heated at 60° C. in a sealed vial for 1 h.Methanesulfonamide (11.9 mg, 0.12 mmol) and DBU (14.1 μL, 0.093 mmol)were added. The reaction mixture was stirred at 60° C. for 1.5 h.Solvents were evaporated and the product was purified via preparativeLC/MS with the following conditions: Column: XBridge C18, 19×200 mm,5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mMammonium acetate; Gradient: 42-82% B over 23 minutes, then a 5-minutehold at 100% B; Flow: 20 mL/min. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to give(E)-4-(6-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-(methylsulfonyl)benzamide(9.0 mg, 52% yield) as white solid. MS (ESI) m/z: 558.1 [M+H]⁺; ¹H NMR(500 MHz, DMSO-d₆) δ 7.77 (d, J=8.6 Hz, 2H).7.66 (d, J=8.0 Hz, 2H), 7.60(dd, J=9.1, 7.0 Hz, 1H), 6.54 (d, J=8.7 Hz, 2H), 6.13 (d, J=16.1 Hz,1H), 5.14 (dd, J=16.1, 8.9 Hz, 1H), 3.58 (d, J=10.2 Hz, 2H), 3.31 (s,3H), 3.20-3.18 (two proton signals were lost due to water suppression),2.44-2.25 (m, 1H), 1.69 (s, 2H), 1.37-1.24 (m, 1H), 1.24-0.99 (m, 4H);HLE GAL-FXR EC₅₀=83 nM.

General Method H Example 116(E)-4-(3-(6-(2-(5-Cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,2,4-oxadiazol-5-yl)benzoicacid

Step 1.(E)-4-(2-(3-Azabicyclo[3.1.0]hexan-6-yl)vinyl)-5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazole

The title compound was prepared according to the procedure described forthe(E)-4-(2-(3-azabicyclo[3.1.0]hexan-6-yl)vinyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole(Step 2 for Example 8) with the replacement of 2,6-dichlorobenzaldehydewith 3,5-dichloroisonicotinaldehyde. MS (ESI) m/z: 362.0 [M+H]⁺.

Step 2.(E)-6-(2-(5-Cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexane-3-carbonitrile

To a mixture of(E)-4-(2-(3-azabicyclo[3.1.0]hexan-6-yl)vinyl)-5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazole(25.0 mg, 0.069 mmol) and potassium carbonate (28.6 mg, 0.21 mmol) inH₂O (0.6 mL) was added a solution of cyanic bromide (8.0 mg, 0.076 mmol)in CH₂Cl₂ (0.6 mL). The reaction mixture was stirred at room temperaturefor 2 h. Aqueous hydrochloric acid solution (0.21 mL, 0.21 mmol, 1M) wasadded, and the mixture was extracted with CH₂Cl₂ (2×8 mL). The organiclayer was dried over MgSO₄, filtered and concentrated in vacuo to give(E)-6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexane-3-carbonitrilethe product as light brown foam solid. MS (ESI) m/z: 387.0 [M+H]⁺; ¹HNMR (400 MHz, CDCl₃) δ 8.63 (s, 2H), 6.06 (dd, J=16.0, 0.7 Hz, 1H), 5.13(dd, J=16.0, 8.4 Hz, 1H), 3.52 (dt, J=9.7, 1.7 Hz, 2H), 3.47 (d, J=9.8Hz, 2H), 2.08 (tt, J=8.4, 5.1 Hz, 1H), 1.56-1.48 (m, 2H), 1.45 (dt,J=8.5, 3.5 Hz, 1H), 1.31-1.08 (m, 4H).

Step 3.(E)-6-((E)-2-(5-Cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-N′-hydroxy-3-azabicyclo[3.1.0]hexane-3-carboximidamide

A mixture of(E)-6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexane-3-carbonitrile(164 mg, 0.42 mmol), hydroxylamine hydrochloride (38.3 mg, 0.55 mmol)and sodium acetate (34.7 mg, 0.42 mmol) in ethanol (6 mL) was heated at60° C. in a sealed vial for 2 h. The solvent was evaporated, thereaction mixture was diluted with water (8 mL), and filtered. Thecollected solid was dried under vacuum to give(E)-6-((E)-2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-N′-hydroxy-3-azabicyclo[3.1.0]hexane-3-carboximidamide(168 mg, 0.40 mmol, 94% yield) as white powder. MS (ESI) m/z: 420.1[M+H]⁺.

Step 4. Methyl(E)-4-(3-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,2,4-oxadiazol-5-yl)benzoate

To a mixture of 4-(methoxycarbonyl)benzoic acid (9.0 mg, 0.050 mmol) inCH₂Cl₂ (1.0 mL) was added HOBT (7.6 mg, 0.050 mmol) and EDC (9.6 mg,0.050 mmol). The reaction mixture was stirred for 1 h.(E)-6-((E)-2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-N′-hydroxy-3-azabicyclo[3.1.0]hexane-3-carboximidamide(20 mg, 0.048 mmol) was added and the mixture was stirred at roomtemperature for 1.5 h. The solvent was evaporated, the resulting whitesolid was taken up in EtOH (1.5 mL), and the resulting mixture washeated in a sealed vial at 85° C. for 5 h. The reaction mixture wascooled to room temperature and concentrated to dryness in vacuo. Theresidue was purified by flash chromatography on SiO₂ (0-40%EtOAc/hexanes) to afford methyl(E)-4-(3-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,2,4-oxadiazol-5-yl)benzoate(15 mg, 57% yield) as white solid. MS (ESI) m/z: 564.1 [M+H]⁺; ¹H NMR(400 MHz, CDCl₃) δ 8.63 (s, 2H), 8.32-7.91 (m, 4H), 6.02 (d, J=15.8 Hz,1H), 5.21 (dd, J=16.0, 8.7 Hz, 1H), 3.96 (s, 3H), 3.79 (d, J=10.2 Hz,2H), 3.53 (dt, J=10.3, 2.0 Hz, 2H), 2.09 (tt, J=8.4, 5.1 Hz, 1H),1.67-1.58 (m, 2H), 1.44-1.35 (m, 1H), 1.30-1.07 (m, 4H).

Example 116.(E)-4-(3-(6-(2-(5-Cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,2,4-oxadiazol-5-yl)benzoicacid

A solution of methyl(E)-4-(3-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,2,4-oxadiazol-5-yl)benzoate(17 mg, 0.030 mmol) in methanol (0.9 mL), THF (0.3 mL) and 1 M aqueoussodium hydroxide (0.12 mL, 0.120 mmol) was heated in a sealed vial at60° C. for 2 h. The volatiles were removed in vacuo and the residue waspurified by preparative HPLC (Column: Sunfire C18 OBD, 30×100 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% TFA; MobilePhase B: 95:5 acetonitrile:water with 0.1% TFA; Gradient: 65-100% B over10 minutes, then a 5-minute hold at 100% B; Flow: 40 mL/min) to afford(E)-4-(3-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,2,4-oxadiazol-5-yl)benzoicacid (7.1 mg, 29% yield) as beige solid. MS (ESI) m/z: 550.1 [M+H]⁺; ¹HNMR (500 MHz, DMSO-d₆) δ 8.86 (s, 2H), 8.13 (s, 4H), 6.16 (d, J=16.0 Hz,1H), 5.29 (dd, J=16.0, 8.8 Hz, 1H), 3.64 (d, J=10.2 Hz, 2H), 3.48 (d,J=9.7 Hz, 2H), 2.43-2.33 (m, 1H), 1.74 (s, 2H), 1.45-1.38 (m, 1H),1.28-0.95 (m, 4H); HLE GAL-FXR EC₅₀=862 nM.

General Method I Example 133(E)-3-(5-(6-(2-(5-Cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,2,4-oxadiazol-3-yl)benzoicacid

Step 1. Methyl(E)-3-(5-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,2,4-oxadiazol-3-yl)benzoate

To a mixture of(E)-6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexane-3-carbonitrile(Step 2 for Example 116, 31 mg, 0.080 mmol), methyl(Z)-3-(N′-hydroxycarbamimidoyl)benzoate (23.3 mg, 0.12 mmol) in ethylacetate (0.7 mL) was slowly added zinc chloride solution (0.24 mL, 0.12mmol, 0.5 M in THF). The reaction mixture was stirred at roomtemperature for 1 h. The solvent was evaporated and the crude productwas treated with ether (1.5 mL). The top clear layer was decanted andthe remaining material was concentrated in vacuo to give a white solid.The solid was suspended in dioxane (0.88 mL), and hydrochloric acidsolution (0.040 mL, 0.16 mmol, 4M in dioxane) was added. The mixture washeated in a sealed vial at 100° C. for 1.5 h. The excess solvent wasevaporated and the residue was diluted with CH₂Cl₂ (5 mL) and washedwith saturated NaHCO₃ solution (1 mL). The organic layer was separatedand concentrated to dryness in vacuo. The residue was purified by flashchromatography on SiO₂ (0-50% EtOAc/hexanes) to give methyl(E)-3-(5-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,2,4-oxadiazol-3-yl)benzoate(20 mg, 45% yield) as white solid. MS (ESI) m/z: 564.2 [M+H]⁺; ¹H NMR(400 MHz, CDCl₃) δ 8.64 (t, J=1.8 Hz, 1H), 8.63 (s, 2H), 8.16 (dt,J=7.9, 1.6 Hz, 1H), 8.13 (dt, J=7.9, 1.6 Hz, 1H), 7.52 (t, J=7.8 Hz,1H), 6.04 (d, J=16.1 Hz, 1H), 5.19 (dd, J=16.0, 8.6 Hz, 1H), 3.94 (s,3H), 3.91 (d, J=10.7 Hz, 2H), 3.74-3.67 (m, 2H), 2.09 (tt, J=8.4, 5.1Hz, 1H), 1.70-1.63 (m, 2H), 1.39-1.31 (m, 1H), 1.30-1.06 (m, 4H).

Example 133.(E)-3-(5-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,2,4-oxadiazol-3-yl)benzoicacid

A solution of methyl(E)-3-(5-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,2,4-oxadiazol-3-yl)benzoate(20 mg, 0.036 mmol) in ethanol (0.9 mL), THF (0.3 mL) and 1 M aqueoussodium hydroxide (0.14 mL, 0.14 mmol) was heated in a sealed vial at 60°C. for 2 h. The volatiles were removed in vacuo and the residue waspurified by preparative HPLC (Column: Sunfire C18 OBD, 30×100 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% TFA; MobilePhase B: 95:5 acetonitrile:water with 0.1% TFA; Gradient: 65-100% B over10 minutes, then a 5-minute hold at 100% B; Flow: 40 mL/min) to give(E)-3-(5-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,2,4-oxadiazol-3-yl)benzoicacid (11.6 mg, 39% yield) as beige solid. MS (ESI) m/z: 550.2 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 8.86 (s, 2H), 8.44 (t, J=1.8 Hz, 1H), 8.10(ddt, J=10.9, 7.8, 1.4 Hz, 2H), 7.65 (t, J=7.8 Hz, 1H), 6.14 (d, J=16.0Hz, 1H), 5.32 (dd, J=16.1, 8.8 Hz, 1H), 3.76 (d, J=10.5 Hz, 2H), 3.70(dt, J=10.5, 1.8 Hz, 2H), 2.38 (tt, J=8.6, 5.2 Hz, 1H), 1.83-1.78 (m,2H), 1.46 (dt, J=8.7, 3.4 Hz, 1H), 1.26-1.01 (m, 4H); HLE GAL-FXREC₅₀=1292 nM.

General Method J1 Example 183(E)-4-Cyclopropoxy-6-(6-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)-isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-2-carboxamide

Step 1.(E)-4-Cyclopropoxy-6-(6-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-2-carbonitrile

A slurry of(E)-4-(2-(3-azabicyclo[3.1.0]hexan-6-yl)vinyl)-5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazole(25 mg, 0.069 mmol), 6-bromo-4-cyclopropoxy quinoline-2-carbonitrile (25mg, 0.086 mmol) and Cs₂CO₃ (90 mg, 0.28 mmol) in dioxane (800 μL) wasdegassed by bubbling nitrogen through the mixture for 5 minutes.Chloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(RuPhos-Pd-G2) (8 mg, 10.3 μmol) was then added and the reaction vesselwas sealed and heated to 105° C. for 2 h. The reaction was filteredthrough a pad of Celite and washed with dichloromethane (3 mL). Thefiltrate was concentrated to give a crude product which was furtherpurified by flash chromatography (silica gel, hexanes:EtOAc, 100:0 to50:50) to afford(E)-4-cyclopropoxy-6-(6-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-2-carbonitrile(35 mg, 0.062 mmol, 89% yield) as yellow foam. ¹H NMR (400 MHz, CDCl₃) δ7.90 (d, J=9.3 Hz, 1H), 7.82 (dd, J=7.6, 1.7 Hz, 1H), 7.69-7.56 (m, 2H),7.41 (dd, J=7.4, 1.7 Hz, 1H), 7.30 (s, 1H), 7.17 (dd, J=9.3, 2.8 Hz,1H), 6.80 (d, J=2.7 Hz, 1H), 6.02 (d, J=16.0 Hz, 1H), 5.16 (dd, J=16.1,8.8 Hz, 1H), 4.04-3.83 (m, 1H), 3.71 (d, J=9.7 Hz, 2H), 3.46 (dt, J=9.9,1.8 Hz, 2H), 2.13-2.03 (m, 1H), 1.75-1.63 (m, 2H), 1.38 (dt, J=8.9, 3.2Hz, 1H), 1.26-1.20 (m, 2H), 1.18-1.09 (m, 2H), 1.05-0.89 (m, 4H); MS(ESI): m/z 569.3 [M+H]⁺.

Example 183.(E)-4-Cyclopropoxy-6-(6-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)-phenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-2-carboxamide

A mixture of(E)-4-cyclopropoxy-6-(6-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-2-carbonitrile(35 mg, 0.062 mmol) in MeOH (1.5 mL) and 6M aqueous potassium hydroxidesolution (0.10 mL, 0.62 mmol) was heated at 120° C. under microwavecondition for 40 min. The pH of the mixture was brought to 4 by addingaqueous conc. HCl. The solvent was evaporated to give the crude product.The crude material was purified via preparative LC/MS with the followingconditions (Column: XBridge C18, 200 mm×19 mm, 5-μm particles; MobilePhase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; MobilePhase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient:a 0-minute hold at 50% B, 50-90% B over 20 minutes, then a 4-minute holdat 100% B; Flow Rate: 20 mL/min; Column Temperature: 25° C.) to affordthe(E)-4-cyclopropoxy-6-(6-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-2-carboxamide(6.0 mg, 35% yield) as an orange powder. ¹H NMR (500 MHz, DMSO-d₆) δ8.00 (bs, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.87-7.62 (m, 4H), 7.48 (d, J=7.5Hz, 1H), 7.34 (bs, 1H), 7.24 (dd, J=9.3, 2.7 Hz, 1H), 6.75 (d, J=2.7 Hz,1H), 6.04 (d, J=16.1 Hz, 1H), 5.19 (dd, J=16.1, 8.8 Hz, 1H), 4.27-3.97(m, 1H), 3.62 (d, J=9.8 Hz, 2H), 3.41-3.27 (m, 2H), 2.26 (td, J=8.5, 4.3Hz, 1H), 1.73-1.64 (m, 2H), 1.36-1.31 (m, 1H), 1.15-1.11 (m, 2H),1.07-1.01 (m, 2H), 0.97-0.90 (m, 2H), 0.84-0.77 (m, 2H); MS (ESI) m/z:587.2 [M+H]⁺. HLE GAL-FXR EC₅₀=908 nM.

General Method J2 Example 184(E)-4-Cyclopropoxy-6-(6-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)-isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-2-carboxylicacid

A mixture of(E)-4-cyclopropoxy-6-(6-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-2-carboxamide(7 mg, 0.012 mmol) in MeOH (1.1 mL) and aqueous 6M potassium hydroxidesolution (110 μL, 0.660 mmol) was heated at 130° C. under microwavecondition for 1 h. Solvent was evaporated. The reaction mixture wasdiluted with CH₂Cl₂ (3 mL) and 4 drops of TFA was added. Solvent wasevaporated to give a crude product which was purified by preparativeHPLC (Column: Sunfire C18 OBD, 30×100 mm, 5-μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 0.1% TFA; Mobile Phase B: 95:5acetonitrile:water with 0.1% TFA; Gradient: 65-100% B over 10 minutes,then a 5-minute hold at 100% B; Flow: 40 mL/min) to afford(E)-4-cyclopropoxy-6-(6-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-2-carboxylicacid (6.24 mg, 70.8% yield) as orange solid: MS (ESI) m/z: 588.3 [M+H]⁺;¹H NMR (400 MHz, Methanol-d₄) δ 8.16 (d, J=9.1 Hz, 1H), 8.06 (s, 1H),7.98-7.83 (m, 1H), 7.83-7.66 (m, 2H), 7.58 (d, J=8.8 Hz, 1H), 7.46 (d,J=7.2 Hz, 1H), 7.03-6.80 (m, 1H), 6.11 (d, J=16.1 Hz, 1H), 5.22 (dd,J=16.0, 8.7 Hz, 1H), 4.47-4.40 (m, 1H), 3.74 (d, J=9.9 Hz, 2H), 3.52 (d,J=10.1 Hz, 2H), 2.24 (tt, J=8.0, 5.2 Hz, 1H), 1.82-1.67 (m, 2H),1.49-1.25 (m, 1H), 1.28-0.79 (m, 8H); HLE GAL-FXR EC₅₀=50 nM.

General Method K Example 208(E)-3-(2-(6-(2-(5-Cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)thiazol-4-yl)-5-methoxybenzoicacid

Step 1.(E)-4-(2-(3-(4-Bromothiazol-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)vinyl)-5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazole

A solution of(E)-4-(2-(3-azabicyclo[3.1.0]hexan-6-yl)vinyl)-5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazole(23 mg, 0.063 mmol), 2,4-dibromothiazole (18 mg, 0.074 mmol) and Et₃N(0.027 mL, 0.190 mmol) in DMF (0.1 mL) was heated at 100° C. in a sealedvial for 2 h. The reaction mixture was filtered through a pad of Celite.The pad was washed with a small amount of dichloromethane. The filtratewas collected and concentrated to give a crude product which waspurified by flash chromatography (silica gel, hexanes:EtOAc, 100:0 to50:50) to afford(E)-4-(2-(3-(4-bromothiazol-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)vinyl)-5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazole(25 mg, 0.048 mmol, 75% yield) as yellow foam solid. ¹H NMR (400 MHz,CDCl₃) δ 8.62 (s, 2H), 6.33 (s, 1H), 6.02 (dd, J=15.9, 0.7 Hz, 1H), 5.17(dd, J=16.0, 8.6 Hz, 1H), 3.66 (d, J=10.2 Hz, 2H), 3.53 (ddd, J=10.2,2.7, 1.5 Hz, 2H), 2.09 (tt, J=8.4, 5.1 Hz, 1H), 1.70-1.61 (m, 2H), 1.34(dt, J=8.7, 3.3 Hz, 1H), 1.27-1.22 (m, 2H), 1.20-1.05 (m, 2H); MS (ESI):m/z 523.0 [M+H]⁺.

Step 2. tert-Butyl(E)-3-(2-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)thiazol-4-yl)-5-methoxybenzoate

A mixture of(E)-4-(2-(3-(4-bromothiazol-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)vinyl)-5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazole(25 mg, 0.048 mmol), tert-butyl3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (19.13mg, 0.057 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (2.337 mg, 2.86 μmol), and 2Maqueous potassium triphosphate solution (0.072 mL, 0.143 mmol) inDioxane (0.8 mL) was heated at 100° C. for 1 h. The mixture was dilutedwith ethyl acetate (5 mL) and filtered through Celite. The filtrate wasconcentrated under vacuum to dryness. The residue was diluted with water(3 mL) and extracted with CH₂Cl₂ (2×10 mL). The combined extract wasdried over anhydrous MgSO₄ and evaporated to dryness to afford a crudeproduct. The crude product was purified by flash chromatography (silicagel, hexanes:EtOAc, 100:0 to 0:100) to afford tert-butyl(E)-3-(2-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)thiazol-4-yl)-5-methoxybenzoate(25 mg, 0.038 mmol, 80% yield) as a white solid: ¹H NMR (400 MHz,Chloroform-d) δ 8.63 (s, 2H), 7.98 (t, J=1.5 Hz, 1H), 7.59 (dd, J=2.7,1.5 Hz, 1H), 7.45-7.40 (m, 1H), 6.74 (s, 1H), 6.02 (d, J=16.1 Hz, 1H),5.20 (dd, J=16.0, 8.7 Hz, 1H), 3.88 (s, 3H), 3.76 (d, J=10.2 Hz, 2H),3.64-3.38 (m, 2H), 2.09 (tt, J=8.4, 5.1 Hz, 1H), 1.70-1.63 (m, 2H), 1.60(s, 9H), 1.41 (dt, J=8.8, 3.3 Hz, 1H), 1.31-1.22 (m, 2H), 1.21-1.06 (m,2H); MS (ESI): m/z 651.2[M+H]⁺.

Example 208.(E)-3-(2-(6-(2-(5-Cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)thiazol-4-yl)-5-methoxybenzoicacid

A mixture of tert-butyl(E)-3-(2-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)thiazol-4-yl)-5-methoxybenzoate(25 mg, 0.038 mmol) in dichloromethane (0.4 mL) and TFA (0.4 mL) wasstirred at rt for 1 h. Solvent was evaporated to give a crude productwhich was purified by preparative HPLC (Column: Sunfire C18 OBD, 30×100mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1%TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.1% TFA;Gradient:30-100% B over 10 minutes, then a 5-minute hold at 100% B;Flow: 40 mL/min) to afford(E)-3-(2-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)thiazol-4-yl)-5-methoxybenzoicacid (17.11 mg, 0.023 mmol, 59.7% yield) as white solid. MS (ESI) m/z:595.1 [M+H]⁺; ¹H NMR (400 MHz, Methanol-d₄) δ 8.73 (s, 2H), 7.98 (t,J=1.5 Hz, 1H), 7.60 (dd, J=2.6, 1.4 Hz, 1H), 7.53 (dd, J=2.5, 1.6 Hz,1H), 7.10 (s, 1H), 6.19 (d, J=16.0 Hz, 1H), 5.30 (dd, J=16.0, 8.5 Hz,1H), 3.91 (s, 3H), 3.80 (d, J=10.5 Hz, 2H), 3.76 (dt, J=10.5, 1.8 Hz,2H), 2.28 (tt, J=8.2, 5.3 Hz, 1H), 1.90-1.81 (m, 2H), 1.47 (dt, J=8.6,3.5 Hz, 1H), 1.29-1.05 (m, 4H); HLE GAL-FXR EC₅₀=247 nM.

General Method L Example 210(E)-3-(3-(6-(2-(5-Cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,2,4-thiadiazol-5-yl)-5-methoxybenzoicacid

Step 1. tert-Butyl(E)-3-(3-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,2,4-thiadiazol-5-yl)-5-methoxybenzoate

A mixture of(E)-4-(2-(3-azabicyclo[3.1.0]hexan-6-yl)vinyl)-5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazole(15 mg, 0.041 mmol), tert-butyl3-(3-chloro-1,2,4-thiadiazol-5-yl)-5-methoxybenzoate (17.59 mg, 0.054mmol) and Et₃N (0.017 mL, 0.124 mmol) in DMF (0.1 mL) was heated at 105°C. for 6 h. Solvent was evaporated to give the crude product which waspurified by flash chromatography (silica gel, hexanes:EtOAc, 100:0 to30: 70) to afford tert-butyl(E)-3-(3-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,2,4-thiadiazol-5-yl)-5-methoxybenzoate(17 mg, 0.026 mmol, 63% yield) as a foam solid. ¹H NMR (400 MHz, CDCl₃)δ 8.63 (s, 2H), 8.01 (t, J=1.4 Hz, 1H), 7.62 (dd, J=2.6, 1.4 Hz, 1H),7.58 (dd, J=2.6, 1.5 Hz, 1H), 6.01 (d, J=16.1 Hz, 1H), 5.22 (dd, J=16.0,8.7 Hz, 1H), 4.01 (d, J=10.5 Hz, 2H), 3.91 (s, 3H), 3.65 (dt, J=10.5,1.8 Hz, 2H), 2.10 (tt, J=8.4, 5.1 Hz, 1H), 1.61 (s, 11H), 1.47-1.37 (m,1H), 1.27-1.21 (m, 2H), 1.18-1.11 (m, 2H). MS (ESI): m/z 652.2[M+H]⁺.

Example 210.(E)-3-(3-(6-(2-(5-Cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,2,4-thiadiazol-5-yl)-5-methoxybenzoicacid

A mixture of tert-butyl(E)-3-(3-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,2,4-thiadiazol-5-yl)-5-methoxybenzoate(15 mg, 0.023 mmol) in dichloromethane (0.4 mL) and TFA (0.4 mL) wasstirred at rt for 1 h. Solvent was evaporated to give a crude productwhich was purified by preparative HPLC (Column: Sunfire C18 OBD, 30×100mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1%TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.1% TFA;Gradient:45-100% B over 10 minutes, then a 5-minute hold at 100% B;Flow: 40 mL/min) to afford(E)-3-(3-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,2,4-thiadiazol-5-yl)-5-methoxybenzoicacid (8.65 mg, 0.012 mmol, 50.3% yield) as white solid: MS (ESI) m/z:596.1 [M+H]⁺; ¹H NMR (400 MHz, Methanol-d₄) δ 8.74 (s, 2H), 8.10 (t,J=1.5 Hz, 1H), 7.73 (dd, J=2.6, 1.4 Hz, 1H), 7.68 (dd, J=2.6, 1.5 Hz,1H), 6.16 (d, J=16.1 Hz, 1H), 5.27 (dd, J=16.0, 8.7 Hz, 1H), 3.97 (d,J=10.6 Hz, 2H), 3.94 (s, 3H), 3.66 (dt, J=10.6, 2.0 Hz, 2H), 2.28 (tt,J=8.2, 5.2 Hz, 1H), 1.76-1.60 (m, 2H), 1.50-1.36 (m, 1H), 1.27-1.09 (m,4H). HLE GAL-FXR EC₅₀=670 nM.

General Method M Example 214(E)-3-(5-(6-(2-(5-Cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,2,4-thiadiazol-3-yl)-5-methoxybenzoicacid

Step 1.(E)-4-(2-(3-(3-Bromo-1,2,4-thiadiazol-5-yl)-3-azabicyclo[3.1.0]hexan-6-yl)vinyl)-5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazole

A mixture of(E)-4-(2-(3-azabicyclo[3.1.0]hexan-6-yl)vinyl)-5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazole(15 mg, 0.041 mmol), 3-bromo-5-chloro-1,2,4-thiadiazole (9 mg, 0.045mmol) and Et₃N (8.66 μL, 0.062 mmol) in THF (0.5 mL) was stirred at rtfor 2 h. Solvent was evaporated to give the crude product which waspurified by flash chromatography (silica gel, hexanes:EtOAc, 100:0 to30: 70) to afford(E)-4-(2-(3-(3-bromo-1,2,4-thiadiazol-5-yl)-3-azabicyclo[3.1.0]hexan-6-yl)vinyl)-5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazole(17 mg, 0.032 mmol, 78% yield) as yellow foam solid: MS (ESI): m/z524.0[M+H].

Step 2. tert-Butyl(E)-3-(5-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,2,4-thiadiazol-3-yl)-5-methoxybenzoate

A mixture of(E)-4-(2-(3-(3-bromo-1,2,4-thiadiazol-5-yl)-3-azabicyclo[3.1.0]hexan-6-yl)vinyl)-5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazole(17 mg, 0.032 mmol), tert-butyl3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (12.98mg, 0.039 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (1.586 mg, 1.942 μmol), and2M aqueous potassium triphosphate solution (0.049 mL, 0.097 mmol) indioxane (0.8 mL) was heated at 100° C. for 1 h. The mixture was dilutedwith ethyl acetate (5 mL) and filtered through Celite. The filtrate wasconcentrated under vacuum to dryness. The residue was diluted with water(3 mL) and extracted with CH₂Cl₂ (3×5 mL). The combined extract wasdried over anhydrous MgSO₄ and evaporated to dryness to afford a crudeproduct. The crude product was purified by flash chromatography (silicagel, hexanes:EtOAc, 100:0 to 10:90) to afford tert-butyl(E)-3-(5-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,2,4-thiadiazol-3-yl)-5-methoxybenzoate(17 mg, 0.026 mmol, 80% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃)δ 8.63 (d, J=0.7 Hz, 3H), 8.37 (t, J=1.4 Hz, 1H), 7.89 (dd, J=2.7, 1.4Hz, 1H), 7.57 (dd, J=2.7, 1.5 Hz, 1H), 6.04 (d, J=16.0 Hz, 2H), 5.20(dd, J=16.0, 8.6 Hz, 1H), 3.90 (s, 3H), 3.81-3.58 (m, 4H), 2.16-2.05 (m,1H), 1.73-1.68 (m, 2H), 1.61 (s, 9H), 1.43-1.35 (m, 1H), 1.25-1.21 (m,2H), 1.21-1.12 (m, 2H).

Example 214.(E)-3-(5-(6-(2-(5-Cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,2,4-thiadiazol-3-yl)-5-methoxybenzoicacid

A mixture of tert-butyl(E)-3-(5-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,2,4-thiadiazol-3-yl)-5-methoxybenzoate(17 mg, 0.026 mmol) in dichloromethane (0.4 mL) and TFA (0.4 mL) wasstirred at rt for 1 h. Solvent was evaporated to give a crude productwhich was purified by preparative HPLC (Column: Sun fire C18 OBD, 30×100mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1%TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.1% TFA;Gradient:45-100% B over 10 minutes, then a 5-minute hold at 100% B;Flow: 40 mL/min) to afford(E)-3-(5-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,2,4-thiadiazol-3-yl)-5-methoxybenzoicacid (5.4 mg, 7.2 μmol, 29% yield) as a white solid. MS (ESI) m/z: 596.1[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.86 (s, 2H), 8.25 (t, J=1.5 Hz,1H), 7.81 (dd, J=2.6, 1.4 Hz, 1H), 7.52 (dd, J=2.6, 1.5 Hz, 1H), 6.15(d, J=16.0 Hz, 1H), 5.33 (dd, J=16.1, 8.8 Hz, 1H), 3.87 (s, 3H),3.81-3.51 (m, 4H), 2.46-2.28 (m, 1H), 1.87-1.77 (m, 2H), 1.44 (dt,J=8.9, 3.4 Hz, 1H), 1.23-1.02 (m, 4H); HLE GAL-FXR EC₅₀=107 nM.

General Method N Example 216(E)-3-(2-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)thiazol-5-yl)-5-methoxybenzoicacid

Step 1.(E)-4-(2-(3-(5-bromothiazol-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)vinyl)-5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazole

A solution of(E)-4-(2-(3-azabicyclo[3.1.0]hexan-6-yl)vinyl)-5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazole(23 mg, 0.063 mmol), 2,5-dibromothiazole (18 mg, 0.074 mmol) and Et₃N(0.027 mL, 0.19 mmol) in DMF (0.1 mL) was heated at 100° C. in a sealedvial for 2 h. Solvent was evaporated to give a crude product which waspurified by flash chromatography (silica gel, hexanes:EtOAc, 100:0 to50:50) to afford(E)-4-(2-(3-(5-bromothiazol-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)vinyl)-5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazole(23 mg, 0.044 mmol, 69% yield) as yellow foam solid. ¹H NMR (400 MHz,CDCl₃) δ 8.62 (s, 2H), 7.03 (s, 1H), 6.02 (dd, J=16.0, 1.4 Hz, 1H), 5.18(dd, J=16.0, 8.6 Hz, 1H), 3.61 (d, J=10.1 Hz, 2H), 3.50 (ddd, J=10.1,2.7, 1.4 Hz, 2H), 2.08 (tt, J=8.4, 5.1 Hz, 1H), 1.71-1.62 (m, 2H), 1.36(dt, J=8.8, 3.4 Hz, 1H), 1.30-1.22 (m, 2H), 1.19-1.07 (m, 2H); MS (ESI):m/z 523.0 [M+H]⁺.

Step 2. tert-Butyl(E)-3-(2-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)thiazol-5-yl)-5-methoxybenzoate

A mixture of(E)-4-(2-(3-(5-bromothiazol-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)vinyl)-5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazole(23 mg, 0.044 mmol), tert-butyl3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (17.60mg, 0.053 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (2.150 mg, 2.63 μmol), and 2Maqueous potassium triphosphate solution (0.061 mL, 0.122 mmol) inDioxane (0.8 mL) was heated at 100° C. for 0.5 h. The mixture wasdiluted with ethyl acetate (5 mL) and filtered through Celite. Thefiltrate was concentrated under vacuum to dryness. The residue wasdiluted with water (3 mL) and extracted with CH₂Cl₂ (3×5 mL). Thecombined extract was dried over anhydrous MgSO₄ and evaporated todryness to afford a crude product. The crude product was purified byflash chromatography (silica gel, hexanes:EtOAc, 100:0 to 20:80) toafford tert-butyl(E)-3-(2-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)thiazol-5-yl)-5-methoxybenzoate(25 mg, 0.038 mmol, 87% yield) as a white solid. ¹H NMR (400 MHz,Chloroform-d) δ 8.63 (s, 2H), 7.61 (t, J=1.5 Hz, 1H), 7.42 (s, 1H), 7.34(dd, J=2.6, 1.3 Hz, 1H), 7.07 (dd, J=2.5, 1.6 Hz, 1H), 6.04 (d, J=15.9Hz, 1H), 5.20 (dd, J=16.0, 8.6 Hz, 1H), 3.86 (s, 3H), 3.72 (d, J=10.2Hz, 2H), 3.61-3.55 (m, 2H), 2.09 (tt, J=8.4, 5.1 Hz, 1H), 1.71-1.65 (m,2H), 1.60 (s, 9H), 1.44-1.36 (m, 1H), 1.30-1.21 (m, 2H), 1.15-1.11 (m,2H); MS (ESI): m/z 651.2[M+H]⁺.

Example 216.(E)-3-(2-(6-(2-(5-Cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)thiazol-5-yl)-5-methoxybenzoicacid

A mixture of tert-butyl(E)-3-(2-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)thiazol-5-yl)-5-methoxybenzoate(25 mg, 0.038 mmol) in dichloromethane (0.4 mL) and TFA (0.4 mL) wasstirred at rt for 1 h. Solvent was evaporated to give a crude productwhich was purified by preparative HPLC (Column: Sunfire C18 OBD, 30×100mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1%TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.1% TFA;Gradient:20-100% B over 10 minutes, then a 5-minute hold at 100% B;Flow: 40 mL/min) to afford(E)-3-(2-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)thiazol-5-yl)-5-methoxybenzoicacid (7.0 mg, 9.4 μmol, 25% yield) as a white solid. MS (ESI) m/z: 595.1[M+H]⁺; ¹H NMR (400 MHz, Methanol-d₄) δ 8.62 (s, 2H), 7.65 (s, 1H), 7.60(t, J=1.5 Hz, 1H), 7.45-7.41 (m, 1H), 7.20 (t, J=2.1 Hz, 1H), 6.08 (d,J=16.0 Hz, 1H), 5.20 (dd, J=16.0, 8.5 Hz, 1H), 3.79 (s, 3H), 3.69 (d,J=11.5 Hz, 2H), 3.65 (d, J=10.5 Hz, 2H), 2.16 (tt, J=8.2, 5.3 Hz, 1H),1.82-1.76 (m, 2H), 1.38 (dt, J=8.8, 3.5 Hz, 1H), 1.17-0.87 (m, 4H); HLEGAL-FXR EC₅₀=202 nM.

Intermediates Methyl 6-bromo-4-(cyclopentyloxy)quinoline-2-carboxylate

Methyl 6-bromo-4-hydroxyquinoline-2-carboxylate (200 mg, 0.71 mmol),iodocyclopentane (0.25 mL, 2.13 mmol) and potassium carbonate (300 mg,2.13 mmol) in acetonitrile (15 mL) were heated to 80° C. After 16 h, thereaction mixture was diluted with water (25 mL) and, extracted withethyl acetate (2×25 mL). The organic layer was dried over Na₂SO₄,filtered, concentrated in vacuo, and purified by flash chromatography onSiO₂ to provide methyl 6-bromo-4-(cyclopentyloxy)quinoline-2-carboxylate(211 mg, 85% yield). MS (ESI) m/z: 352.0 [M+H]+; ¹H NMR (500 MHz, CDCl₃)δ 8.37 (d, J=2.2 Hz, 1H), 8.10 (d, J=9.1 Hz, 1H), 7.83 (dd, J=8.8, 2.2Hz, 1H), 7.59 (s, 1H), 5.15 (dt, J=5.6, 3.0 Hz, 1H), 4.10 (s, 3H),2.18-2.09 (m, 2H), 2.08-2.01 (m, 2H), 1.97-1.88 (m, 2H), 1.81-1.65 (m,2H).

Methyl 6-bromo-4-(2,2-difluoroethoxy)quinoline-2-carboxylate

Methyl 6-bromo-4-(2,2-difluoroethoxy)quinoline-2-carboxylate wasprepared following the procedure described for the preparation of methyl6-bromo-4-(cyclopentyloxy)quinoline-2-carboxylate with replacement ofiodocyclopentane with 1,1-difluoro-2-iodoethane (60% yield). MS (ESI)m/z: 345.9 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 8.22-8.36 (m, 1H), 8.03 (d,J=9.02 Hz, 1H), 7.78 (dd, J=2.20, 9.02 Hz, 1H), 7.50 (s, 1H), 6.00-6.48(m, 1H), 4.43 (dt, J=3.96, 12.76 Hz, 2H), 4.01 (s, 3H).

Methyl 6-bromo-4-(2-methoxyethoxy)quinoline-2-carboxylate

Methyl 6-bromo-4-(2-methoxyethoxy)quinoline-2-carboxylate was preparedfollowing the procedure described for the preparation of methyl6-bromo-4-(cyclopentyloxy)quinoline-2-carboxylate with replacement ofiodocyclopentane with 1-bromo-2-methoxyethane (79% yield). MS (ESI) m/z:340.08 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃) δ 8.46 (d, J=1.9 Hz, 1H), 8.11(d, J=9.1 Hz, 1H), 7.85 (dd, J=9.1, 2.2 Hz, 1H), 7.63 (s, 1H), 4.51-4.42(m, 2H), 4.10 (s, 3H), 3.98-3.91 (m, 2H), 3.54 (s, 3H).

Methyl 6-bromo-4-(2-hydroxyethoxy)quinoline-2-carboxylate

Methyl 6-bromo-4-(2-hydroxyethoxy)quinoline-2-carboxylate was preparedfollowing the procedure described for the preparation of methyl6-bromo-4-(cyclopentyloxy)quinoline-2-carboxylate with replacement ofiodocyclopentane with 2-bromoethan-1-ol (88% yield). MS (ESI) m/z:326.08 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.52 (d, J=2.2 Hz, 1H),8.09-8.01 (m, 1H), 8.00-7.94 (m, 1H), 7.60-7.56 (m, 1H), 4.36 (t, J=4.5Hz, 2H), 3.95 (s, 3H), 3.92-3.84 (m, 2H).

Methyl 6-bromo-4-cyclobutoxy quinoline-2-carboxylate

Methyl 6-bromo-4-cyclobutoxyquinoline-2-carboxylate was preparedfollowing the procedure described for the preparation of methyl6-bromo-4-(cyclopentyloxy)quinoline-2-carboxylate with replacement ofiodocyclopentane with bromocyclobutane (54% yield). MS (ESI) m/z: 336.08[M+H]⁺; MS (ESI) m/z: 336.08 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃) δ 8.43 (d,J=1.9 Hz, 1H), 8.10 (d, J=9.1 Hz, 1H), 7.84 (dd, J=8.8, 2.2 Hz, 1H),7.45 (s, 1H), 5.05-4.96 (m, 1H), 4.09 (s, 3H), 2.73-2.59 (m, 2H), 2.44(br d, J=9.1 Hz, 2H), 2.07-1.95 (m, 1H), 1.92-1.77 (m, 1H).

Methyl (R)-6-bromo-4-((tetrahydrofuran-3-yl)oxy)quinoline-2-carboxylate

Step 1. (S)-Tetrahydrofuran-3-yl 4-methylbenzenesulfonate

To a mixture of (S)-tetrahydrofuran-3-ol (1 g, 11.35 mmol) and pyridine(1.8 mL, 22.7 mmol) in CH₂Cl₂ (20 mL) was added p-toluenesulfonylchloride (3.3 g, 17.3 mmol) at room temperature. The reaction mixturewas stirred at this temperature for 2 h. After evaporation of thesolvents, the crude product was diluted with EtOAc (50 mL), washed withwater, then 1 N HCl. The organic layer was dried over MgSO₄, filteredand concentrated in vacuo. The residue was purified by flashchromatography on SiO₂ (0-50% EtOAc/hexanes) to afford(S)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (1.9 g, 69% yield) asa colorless oil. MS (ESI): m/z 243.1 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ7.81 (d, J=8.1 Hz, 2H), 7.37 (d, J=8.1 Hz, 2H), 5.14 (tt, J=4.8, 2.5 Hz,1H), 3.99-3.75 (m, 4H), 2.48 (s, 3H), 2.17-2.05 (m, 2H).

Step 2. Methyl(R)-6-bromo-4-((tetrahydrofuran-3-yl)oxy)quinoline-2-carboxylate

The title compound was prepared following the procedure described forthe preparation of methyl6-bromo-4-(cyclopentyloxy)quinoline-2-carboxylate with replacement ofiodocyclopentane with (S)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate(190 mg, 73% yield) as white solid. MS (ESI) m/z: 352.0 [M+H]⁺; ¹H NMR(400 MHz, CDCl₃) δ 8.38 (d, J=2.3 Hz, 1H), 8.09 (d, J=9.0 Hz, 1H), 7.84(dd, J=9.0, 2.2 Hz, 1H), 7.52 (s, 1H), 5.34-5.25 (m, 1H), 4.20-4.14 (m,2H), 4.14-3.95 (m, 2H), 4.08 (s, 3H), 2.56-2.17 (m, 2H).

Methyl (S)-6-bromo-4-((tetrahydrofuran-3-yl)oxy)quinoline-2-carboxylate

The title compound was prepared following the procedure described forthe preparation of methyl(R)-6-bromo-4-((tetrahydrofuran-3-yl)oxy)quinoline-2-carboxylate withreplacement of (S)-tetrahydrofuran-3-ol with (R)-tetrahydrofuran-3-ol.MS (ESI) m/z: 352.0 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 8.38 (d, J=2.2 Hz,1H), 8.09 (d, J=9.0 Hz, 1H), 7.84 (dd, J=9.0, 2.2 Hz, 1H), 7.52 (s, 1H),5.32-5.25 (m, 1H), 4.19-4.14 (m, 2H), 4.13-3.93 (m, 2H), 4.08 (s, 3H),2.52-2.22 (m, 2H).

(±) Methyl-6-bromo-4-((tetrahydrofuran-3-yl)oxy)quinoline-2-carboxylate

The title compound was prepared following the procedure described forthe preparation of methyl(R)-6-bromo-4-((tetrahydrofuran-3-yl)oxy)quinoline-2-carboxylate withreplacement of (S)-tetrahydrofuran-3-ol with (+)-tetrahydrofuran-3-ol.MS (ESI) m/z: 352.0 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 8.38 (d, J=2.2 Hz,1H), 8.10 (d, J=9.0 Hz, 1H), 7.85 (dd, J=9.0, 2.3 Hz, 1H), 7.53 (s, 1H),5.31-5.26 (m, 1H), 4.20-4.14 (m, 2H), 4.13-3.96 (m, 2H), 4.09 (s, 3H),2.52-2.25 (m, 2H).

Methyl 6-bromo-4-(oxetan-3-yloxy)quinoline-2-carboxylate

A mixture of methyl 6-bromo-4-hydroxyquinoline-2-carboxylate (0.44 g,1.6 mmol), 3-iodooxetane (0.53 g, 2.9 mmol) and K₂CO₃ (0.64 g, 4.7 mmol)in DMF (8 mL) was heated at 85° C. in a sealed vial for 6 h. Anotherportion of 3-iodooxetane (0.20 g, 1.1 mmol) and K₂CO₃ (0.1 g, 0.72 mmol)was added. The reaction mixture was heated at 85° C. in a sealed vialfor another 16 h. The reaction mixture was cooled to room temperature,diluted with CH₂Cl₂ (20 mL) and filtered. The filtrate was concentratedin vacuo and the residue was purified by flash chromatography on SiO₂(0-80% EtOAc/hexanes) to afford methyl6-bromo-4-(oxetan-3-yloxy)quinoline-2-carboxylate (0.29 g, 54% yield) aswhite solid. MS (ESI) m/z: 340.0 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 8.45(d, J=2.2 Hz, 1H), 8.11 (d, J=9.0 Hz, 1H), 7.87 (dd, J=9.0, 2.3 Hz, 1H),7.16 (s, 1H), 5.54 (tt, J=6.0, 4.9 Hz, 1H), 5.15 (ddd, J=7.2, 6.0, 1.0Hz, 2H), 4.90 (ddd, J=7.6, 5.0, 1.0 Hz, 2H), 4.07 (s, 3H).

Methyl 6-bromo-4-(3,3-difluorocyclobutoxy)quinoline-2-carboxylate

A mixture of methyl 6-bromo-4-hydroxyquinoline-2-carboxylate (0.30 g,1.1 mmol), 3-bromo-1,1-difluorocyclobutane (0.25 g, 1.4 mmol), andpotassium carbonate (0.37 g, 2.7 mmol) in DMF (10 mL) was heated at 80°C. for 20 h. The reaction mixture was diluted with ethyl acetate (20 mL)and filtered through Celite. The filtrate was diluted with ethyl acetate(80 mL) and subsequently washed with water (3×25 mL) and brine (25 mL).The organic layer was dried over MgSO₄, filtered and concentrated todryness in vacuo. The residue was loaded onto an Isco solid loadcartridge and purified by flash chromatography on SiO₂ (20-60%EtOAc/hexanes) to give methyl6-bromo-4-(3,3-difluorocyclobutoxy)quinoline-2-carboxylate (40 mg, 0.11mmol, 10% yield) as a white solid. MS (ESI) m/z: 372.1 [M+H]⁺.

Methyl 6-bromo-4-(difluoromethoxy)quinoline-2-carboxylate

To a stirred suspension of Cs₂CO₃ (0.98 g, 3.0 mmol) in DMF (5 mL) at 0°C. was added methyl 6-bromo-4-hydroxyquinoline-2-carboxylate (0.28 g,1.0 mmol) and sodium chlorodifluoroacetate (0.46 g, 3.0 mmol). Thereaction mixture was stirred with heating at 80° C. for 30 minutes.After cooling the reaction mixture to room temperature, water (25 mL)was added, and the resulting suspension was stirred for 1 h. The solidwas collected by suction filtration and washed with water (2×5 mL).After drying under vacuum overnight, methyl6-bromo-4-(difluoromethoxy)quinoline-2-carboxylate (0.28 g, 0.81 mmol,81% yield) was obtained as a white solid. MS (ESI) m/z: 333.9 [M+H]⁺; ¹HNMR (400 MHz, CDCl₃) δ 8.38 (d, J=2.20 Hz, 1H), 8.16 (d, J=9.02 Hz, 1H),7.91 (dd, J=2.20, 9.24 Hz, 1H), 7.85 (t, J=1.10 Hz, 1H), 6.61-7.17 (m,1H), 4.09 (s, 3H).

Methyl 7-chloro-1-methylisoquinoline-3-carboxylate

Step 1. Methyl(R)-7-chloro-1-methyl-3,4-dihydroisoquinoline-3-carboxylate

To a solution of methyl (R)-2-acetamido-3-(4-chlorophenyl)propanoate(0.61 g, 2.37 mmol) in dichloromethane (15.8 mL) at 0° C. was addedoxalyl dichloride (1.42 mL, 2.8 mmol) dropwise. The mixture was stirredat 0° C. for 1 h and room temperature for 1 h. The reaction was cooledto 0° C., and iron (III) chloride (0.46 g, 2.8 mmol) was addedportionwise. The mixture was allowed to warm to room temperature,stirred at for 1.5 h, filtered through a pad of SiO₂, and concentratedin vacuo. The oily residue was purified by flash chromatography on SiO₂(0-60% EtOAc/hexanes) to give methyl(R)-7-chloro-1-methyl-3,4-dihydroisoquinoline-3-carboxylate (0.62 g, 2.0mmol, 84% yield) as an oil. MS (ESI) m/z: 238.0 (M+H)⁺.

Step 2. Methyl 7-chloro-1-methylisoquinoline-3-carboxylate

A mixture of methyl(R)-7-chloro-1-methyl-3,4-dihydroisoquinoline-3-carboxylate (0.60 g, 1.9mmol) and 10% Pd—C (0.62 g, 0.58 mmol) in DCE (4.9 mL) in a sealed tubewas heated at 110° C. for 4 h. The reaction mixture was loaded onto aSiO₂ solid cartridge and purified by flash chromatography on SiO₂ (0-50%EtOAc/hexanes) to give methyl7-chloro-1-methylisoquinoline-3-carboxylate (110 mg, 0.47 mmol, 24%yield) as a tan solid. MS (ESI) m/z: 236.0 (M+H)⁺; ¹H NMR (400 MHz,CDCl₃) δ 8.44 (s, 1H), 8.16-8.19 (m, 1H), 7.92 (d, J=8.58 Hz, 1H), 7.72(dd, J=1.98, 8.80 Hz, 1H), 4.06 (s, 3H), 3.03 (s, 3H).

Ethyl 7-bromo-1-methoxyisoquinoline-3-carboxylate

Step 1. 7-Bromo-3-(ethoxycarbonyl)isoquinoline 2-oxide

To a solution of ethyl 7-bromoisoquinoline-3-carboxylate (0.46 g, 1.6mmol) in dichloromethane (10 mL) at 0° C. was added3-chlorobenzoperoxoic acid (0.55 g, 2.4 mmol) in one portion. Theresulting solution was stirred at room temperature for 22 h, quenchedwith saturated aqueous NaHCO₃ (20 mL) and extracted with dichloromethane(3×40 mL). The combined extracts were dried over Na₂SO₄, filtered andconcentrated in vacuo to dryness. The residue was loaded onto an Iscosolid load cartridge and purified by flash chromatography on SiO₂(60-95% EtOAc/hexanes) to give 7-bromo-3-(ethoxycarbonyl)isoquinoline2-oxide (0.34 g, 1.1 mmol, 70% yield) as a white solid. MS (ESI) m/z:297.9 (M+H)⁺.

Step 2. Ethyl 7-bromo-1-chloroisoquinoline-3-carboxylate

A mixture of 7-bromo-3-(ethoxycarbonyl)isoquinoline 2-oxide (0.19 g,0.64 mmol) and phosphoryl trichloride (4.0 mL, 42.9 mmol) was heated at100° C. for 3 h. The reaction mixture was cooled to room temperature andconcentrated under vacuum to dryness. The residue was dissolved inacetonitrile and purified by preparative HPLC (Column: Phenomenex LunaAxia 5u C18 21.2×100. Solvent A: 90% H₂O-10% ACN-0.1% TFA; Solvent B:10% ACN-90% H₂O 0.1% TFA. 16 minute linear gradient from 32-100% B inA). The product containing fractions were combined, neutralized withsaturated aqueous NaHCO₃, concentrated under vacuum, and extracted withdichloromethane (3×30 mL). The combined extracts were dried over Na₂SO₄,filtered and concentrated in vacuo to give ethyl7-bromo-4-chloroisoquinoline-3-carboxylate (61 mg, 0.19 mmol, 30% yield)as a white solid. MS (ESI) m/z: 313.9 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆)δ 8.75 (s, 1H), 8.52 (s, 1H), 8.33 (d, J=8.8 Hz, 1H), 8.19 (dd, J=8.8,1.9 Hz, 1H), 4.42 (q, J=7.1 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H).

Step 3. Ethyl 7-bromo-1-methoxyisoquinoline-3-carboxylate

To a suspension of ethyl 7-bromo-1-chloroisoquinoline-3-carboxylate(0.13 g, 0.43 mmol) in MeOH (5 mL) at 0° C. was added sodium methoxidein MeOH (0.32 mL, 1.7 mmol) dropwise. The resulting mixture was stirredat room temperature for 3 h. Additional sodium methoxide in MeOH (0.32mL, 1.7 mmol) was added and the mixture was stirred for another 2 h. Thereaction mixture was cooled to 0° C., quenched with saturated aqueousNH₄Cl (10 mL) and the resulting mixture was extracted withdichloromethane (4×30 mL). The combined organic extracts were dried overMgSO₄, filtered and concentrated in vacuo. The residue was loaded ontoan Isco solid load cartridge and purified by flash chromatography onSiO₂ (8-25% EtOAc/hexanes) to give methyl7-bromo-1-methoxyisoquinoline-3-carboxylate (80 mg, 0.27 mmol, 63%yield) as a white solid. MS (ESI) m/z: 295.9 [M+H]⁺.

Methyl 2-bromo-7-methylthiazolo[5,4-b]pyridine-5-carboxylate

Step 1. 5-Chloro-7-methylthiazolo[5,4-b]pyridin-2-amine

To a mixture of 2,6-dichloro-4-methylpyridin-3-amine (0.50 g, 2.8 mmol)and potassium thiocyanate (0.82 g, 8.5 mmol) in ethanol (7.5 mL) at roomtemperature was added concentrated hydrochloric acid (10.0 mL, 330 mmol)dropwise. The mixture was heated at 100° C. for 44 h. Additionalpotassium thiocyanate (0.82 g, 8.5 mmol) was added, and the mixture washeated at 100° C. for additional 31 h. The reaction mixture was cooledto room temperature and concentrated under vacuum to dryness. To theresidue was added 1 N aqueous NaOH (10 mL) followed by solid K₂CO₃ untilthe mixture became basic (pH=9-10). The mixture was extracted withdichloromethane (4×40 mL). The combined organic extracts were dried overanhydrous Na₂SO₄, filtered and concentrated to dryness in vacuo. Theresidue was loaded onto an Isco solid load cartridge and purified byflash chromatography on SiO₂ (0-6% MeOH/DCM) to give5-chloro-7-methylthiazolo[5,4-b]pyridin-2-amine (0.33 g, 1.7 mmol, 59%yield) as a tan solid. MS (ESI) m/z: 199.9 [M+H]⁺; ¹H NMR (500 MHz,DMSO-d₆) δ 7.90 (s, 2H), 7.22 (s, 1H), 2.41 (s, 3H).

Step 2. tert-Butyl(5-chloro-7-methylthiazolo[5,4-b]pyridin-2-yl)carbamate

To a suspension of 5-chloro-7-methylthiazolo[5,4-b]pyridin-2-amine (0.33g, 1.65 mmol) in dichloromethane (8 mL) at 0° C. was added di-tert-butyldicarbonate (0.54 g, 2.5 mmol) in dichloromethane (2 mL), followed byDMAP (0.030 g, 0.25 mmol). The heterogeneous mixture was stirred at roomtemperature for 1 h giving a homogeneous solution. The solution wasdiluted with dichloromethane (120 mL), washed with water (2×25 mL) andbrine (25 mL). The organic layer was dried over anhydrous MgSO₄,filtered and concentrated to dryness in vacuo. The residue was loadedonto an Isco solid load cartridge and purified by flash chromatographyon SiO₂ (5-35% EtOAc/hexanes) to give tert-butyl(5-chloro-7-methylthiazolo[5,4-b]pyridin-2-yl)carbamate (0.40 g, 1.3mmol, 82% yield) as a beige solid.

Step 3. Methyl2-((tert-butoxycarbonyl)amino)-7-methylthiazolo[5,4-b]pyridine-5-carboxylate

A mixture of tert-butyl(5-chloro-7-methylthiazolo[5,4-b]pyridin-2-yl)carbamate (0.40 g, 1.3mmol), methanol (15 mL, 1.3 mmol), 1,3-bis(diphenylphosphanyl)propane(0.067 g, 0.16 mmol), palladium(II) acetate (0.036 g, 0.16 mmol), andpotassium carbonate (0.30 g, 2.2 mmol) was heated under CO (50 psi) in apressure bottle at 90° C. for 16 h. The reaction mixture was cooled toroom temperature, diluted with ethyl acetate (40 mL) and filteredthrough Celite. The filtrate was concentrated under vacuum to dryness.To the residue was added water (15 mL), and the resulting beige solidwas collected by suction filtration. The solid was loaded onto an Iscosolid load cartridge and purified by flash chromatography on SiO₂(10-50% EtOAc/hexanes) to give methyl2-((tert-butoxycarbonyl)amino)-7-methylthiazolo[5,4-b]pyridine-5-carboxylate(0.28 g, 0.86 mmol, 64% yield) as a beige solid. MS (ESI) m/z: 324.0[M+H]⁺.

Step 4. Methyl 2-amino-7-methylthiazolo[5,4-b]pyridine-5-carboxylate

To a suspension of methyl2-((tert-butoxycarbonyl)amino)-7-methylthiazolo[5,4-b]pyridine-5-carboxylate(0.28 g, 0.86 mmol) in dichloromethane (6 mL) at 0° C. was added TFA (6mL, 78 mmol) over 2 min. The resulting solution was stirred at roomtemperature for 1.5 h and concentrated under vacuum to dryness. To theresidue was added saturated aqueous NaHCO₃ (10 mL) and the resultingprecipitate was collected and dried under vacuum to give methyl2-amino-7-methylthiazolo[5,4-b]pyridine-5-carboxylate (0.16 g, 0.73mmol, 85% yield) as a beige solid. MS (ESI) m/z: 223.9 [M+H]⁺; ¹H NMR(500 MHz, DMSO-d₆) δ 8.22 (s, 2H), 7.84 (s, 1H), 3.85 (s, 3H), 2.47 (s,3H).

Step 5. Methyl 2-bromo-7-methylthiazolo[5,4-b]pyridine-5-carboxylate

To a mixture of copper(II) bromide (0.20 g, 0.90 mmol) in acetonitrile(7 mL) at 0° C. was added tert-butyl nitrite (0.15 mL, 1.3 mmol)dropwise, followed by methyl2-amino-7-methylthiazolo[5,4-b]pyridine-5-carboxylate (0.16 g, 0.72mmol) portionwise. The reaction mixture was stirred at room temperaturefor 6 h, diluted with ethyl acetate (15 mL) and filtered through Celite.The filtrate was concentrated under vacuum. The residue was loaded ontoan Isco solid load cartridge and purified by flash chromatography onSiO₂ (20-80% EtOAc/hexanes, Isco 40 g column) to give methyl2-bromo-7-methylthiazolo[5,4-b]pyridine-5-carboxylate (74 mg, 0.26 mmol,36% yield) as a tan solid. (ESI) m/z: 286.8 [M+H]⁺.

Methyl 2-bromo-7-methoxythiazolo[5,4-b]pyridine-5-carboxylate

Step 1. 5-Chloro-7-methoxythiazolo[5,4-b]pyridin-2-amine

To a mixture of 6-chloro-4-methoxypyridin-3-amine (0.50 g, 3.1 mmol) andpotassium isothiocyanate (0.61 g, 6.3 mmol) in acetic acid (5 mL) atroom temperature was added bromine (0.18 mL, 3.4 mmol) in acetic acid (2mL) over 30 min. The mixture was stirred at room temperature for 16 hbefore additional potassium isothiocyanate (0.61 g, 6.3 mmol) and aceticacid (1 mL) were added. The mixture was stirred at room temperature for24 h. To the mixture was added water (100 mL) and the mixture wasstirred for 2 h. The insoluble material was collected by suctionfiltration and the filter cake was suspended in water (100 mL) andstirred for 2 h. The solid was collected by suction filtration and driedunder vacuum at 50° C. to give5-chloro-7-methoxythiazolo[5,4-b]pyridin-2-amine (0.70 g, 3.1 mmol, 100%yield) as a tan solid. MS (ESI) m/z: 215.9 [M+H]⁺; 1H NMR (500 MHz,DMSO-d₆) δ 7.74 (br s, 2H), 7.02 (s, 1H), 3.94 (s, 3H).

Step 2. 5-Chloro-2-bis(Boc)amino-7-methoxythiazolo[5,4-b]pyridine

To a suspension of 5-chloro-7-methoxythiazolo[5,4-b]pyridin-2-amine(0.70 g, 3.1 mmol) in dichloromethane (15 mL) at 0° C. was addeddi-tert-butyl dicarbonate (2.0 g, 9.4 mmol) in dichloromethane (5 mL),followed by DMAP (0.076 g, 0.62 mmol). The heterogeneous mixture washeated at reflux for 2 h. The mixture was diluted with dichloromethane(250 mL) and washed with water (40 mL). The aqueous layer was extractedwith dichloromethane (2×30 mL). The combined organic phase was driedover anhydrous Na₂SO₄, filtered and concentrated to dryness in vacuo.The residue was loaded onto an Isco solid load cartridge and purified byflash chromatography on SiO₂ (10-30% EtOAc/hexanes, Isco 40 g column) togive 5-chloro-2-bis(Boc)amino-7-methoxythiazolo[5,4-b]pyridine (0.54 g,1.3 mmol, 42% yield) as a white solid. MS (ESI) m/z: 416.1 [M+H]⁺; ¹HNMR (500 MHz, DMSO-d₆) δ 7.27 (s, 1H), 4.05 (s, 3H), 1.55 (s, 18H).

Step 3. Methyl2-((tert-butoxycarbonyl)amino)-7-methoxythiazolo[5,4-b]pyridine-5-carboxylate

A mixture of 5-chloro-2-bis(Boc)amino-7-methoxythiazolo[5,4-b]pyridine(0.54 g, 1.3 mmol), methanol (11 mL, 1.3 mmol),1,3-bis(diphenylphosphanyl)propane (0.080 g, 0.20 mmol), palladium(II)acetate (0.044 g, 0.20 mmol), and potassium carbonate (0.32 g, 2.3 mmol)in DMF (3.5 mL) was heated under CO (50 psi) in a pressure bottle at 90°C. for 7 h. The mixture was diluted with ethyl acetate (30 mL), filteredthrough Celite and concentrated under vacuum to dryness. To the residuewas added water (20 mL), and the mixture was extracted withdichloromethane (4×40 mL). The combined extracts were washed with water(3×25 mL), dried over anhydrous Na₂SO₄, filtered and concentrated todryness in vacuo. The residue was loaded onto an Isco solid loadcartridge and purified by flash chromatography on SiO₂ (30-80%EtOAc/hexanes, Isco 40 g column) to give methyl2-((tert-butoxycarbonyl)amino)-7-methoxythiazolo[5,4-b]pyridine-5-carboxylate(0.20 g, 0.58 mmol, 44% yield). MS (ESI) m/z: 340.0 [M+H]⁺; ¹H NMR (500MHz, DMSO-d₆) δ 12.16 (s, 1H), 7.68 (s, 1H), 4.06 (s, 3H), 3.91 (s, 3H),1.53 (s, 9H).

Step 4. Methyl 2-amino-7-methoxythiazolo[5,4-b]pyridine-5-carboxylate

To a suspension of methyl2-((tert-butoxycarbonyl)amino)-7-methoxythiazolo[5,4-b]pyridine-5-carboxylate(0.26 g, 0.76 mmol) in dichloromethane (5 mL) at 0° C. was added TFA (5mL, 65 mmol) over 2 min. The resulting solution was stirred for 1.5 hand then concentrated under vacuum to dryness. To the residue was addedsaturated NaHCO₃ solution (10 mL). The resulting solid was collected anddried at 50° C. under vacuum to give methyl2-amino-7-methoxythiazolo[5,4-b]pyridine-5-carboxylate (0.160 g, 0.669mmol, 88% yield) as a beige solid. MS (ESI) m/z: 240.0 [M+H]⁺; ¹H NMR(500 MHz, DMSO-d₆) δ 8.05 (s, 2H), 7.57 (s, 1H), 3.98 (s, 3H), 3.86 (s,3H).

Step 5. Methyl 2-bromo-7-methoxythiazolo[5,4-b]pyridine-5-carboxylate

To a mixture of copper(II) bromide (0.18 g, 0.82 mmol) in acetonitrile(6 mL) at 0° C. was added tert-butyl nitrite (0.16 mL, 1.3 mmol)dropwise, followed by methyl2-amino-7-methoxythiazolo[5,4-b]pyridine-5-carboxylate (0.16 g, 0.66mmol) portionwise. The mixture was stirred at 0° C. for 1 h and then atroom temperature for 4 h. The yellow insoluble material was collected asthe first crop of product (0.17 g) by suction filtration. The filtratewas diluted with dichloromethane (50 mL), washed with water (2×15 mL),dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. Theresidue was loaded onto an Isco solid load cartridge and purified byflash chromatography on SiO₂ (10-40% EtOAc/hexanes, Isco 40 g column)give a second crop of methyl2-bromo-7-methoxythiazolo[5,4-b]pyridine-5-carboxylate (67 mg) as a palesolid. MS (ESI) m/z: 302.9 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 7.78 (brs, 1H), 4.13 (s, 3H), 3.93 (s, 3H).

Methyl 2-bromothiazolo[5,4-b]pyridine-5-carboxylate

Step 1. tert-Butyl (5-chlorothiazolo[5,4-b]pyridin-2-yl)carbamate

To a suspension of 5-chlorothiazolo[5,4-b]pyridin-2-amine (0.53 g, 2.8mmol) in dichloromethane (10 mL) at 0° C. was added di-tert-butyldicarbonate (0.93 g, 4.3 mmol) followed by DMAP (0.069 g, 0.57 mmol).The heterogeneous mixture was stirred at room temperature for 3.5 h andthen concentrated under vacuum to dryness. To the residue was addedhexane (10 mL) and the resulting solid was collected by suctionfiltration to give, tert-butyl(5-chlorothiazolo[5,4-b]pyridin-2-yl)carbamate (0.58 g, 2.0 mmol, 71%yield), as a white solid.

Step 2. Methyl2-((tert-butoxycarbonyl)amino)thiazolo[5,4-b]pyridine-5-carboxylate

A mixture of tert-butyl (5-chlorothiazolo[5,4-b]pyridin-2-yl)carbamate(0.30 g, 1.0 mmol), 1,3-bis(diphenylphosphanyl)propane (0.052 g, 0.13mmol), palladium(II) acetate (0.028 g, 0.13 mmol), and potassiumcarbonate (0.23 g, 1.7 mmol) in methanol (5 mL) and DMF (2.5 mL) washeated under CO (48 psi) in a pressure bottle at 85° C. for 7.5 h. Themixture was diluted with ethyl acetate (30 mL) and filtered throughCelite. The filtrate was concentrated under vacuum to dryness. Theresidue was dissolved in ethyl acetate (100 mL) and washed with water(20 mL). The aqueous layer was separated and the desired productcrystallized from the aqueous layer. The solid was collected by suctionfiltration to give a first crop of methyl2-((tert-butoxycarbonyl)amino)thiazolo[5,4-b]pyridine-5-carboxylate (126mg, 39%) as a white solid. The organic layer was dried over anhydrousNa₂SO₄, filtered, and concentrated under vacuum. The residue waspurified by flash chromatograph on SiO₂ (20-80% ethyl EtOAc/hexanes,Isco 40 g column) to give a second crop of methyl2-((tert-butoxycarbonyl)amino)thiazolo[5,4-b]pyridine-5-carboxylate(0.090 g, 28%). MS (ESI) m/z: 310.0 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ12.25 (br s, 1H), 8.29-8.00 (m, 2H), 3.91 (s, 3H), 1.54 (s, 9H).

Step 3. Methyl 2-aminothiazolo[5,4-b]pyridine-5-carboxylate

To a suspension of methyl2-((tert-butoxycarbonyl)amino)thiazolo[5,4-b]pyridine-5-carboxylate(0.212 g, 0.685 mmol) in dichloromethane (5 mL) at 0° C. was added TFA(5 mL, 64.9 mmol) over 2 min. The resulting solution was stirred at roomtemperature for 1 h and then concentrated under vacuum to dryness. Tothe residue was added saturated NaHCO₃ solution (7 mL) and the resultingsolid was collected by suction filtration and dried in vacuo at 50° C.to give methyl 2-aminothiazolo[5,4-b]pyridine-5-carboxylate (0.128 g,0.612 mmol, 89% yield), as a white solid. MS (ESI) m/z: 209.9 [M+H]⁺.

Step 4. Methyl 2-bromothiazolo[5,4-b]pyridine-5-carboxylate

To copper(II) bromide (0.17 g, 0.76 mmol) in acetonitrile (6 mL) at 0°C. was added tert-butyl nitrite (0.13 mL, 1.1 mmol) followed by methyl2-aminothiazolo[5,4-b]pyridine-5-carboxylate (128 mg, 0.61 mmol). Themixture was stirred at room temperature for 18 h. Additional copper (II)bromide (0.17 g, 0.76 mmol) and tert-butyl nitrite (0.13 mL, 1.1 mmol)were added, and the mixture was stirred at room temperature for 4 h. Athird portion of tert-butyl nitrite (0.065 mL, 0.55 mmol) was added andthe mixture was stirred at room temperature for 4 h. Another portion oftert-butyl nitrite (0.060 mL, 0.54 mmol) was added and the mixture wasstirred at room temperature for 2 h. The mixture was diluted with ethylacetate (25 mL) and filtered through Celite. The filtrate wasconcentrated under vacuum and the residue was purified by flashchromatograph on SiO₂ (20-80% EtOAc/hexanes, Isco 40 g column) to givemethyl 2-bromothiazolo[5,4-b]pyridine-5-carboxylate (90 mg, 0.33 mmol,54% yield) as a beige solid. MS (ESI) m/z: 272.8 [M+H]⁺; ¹H NMR (500MHz, DMSO-d₆) δ 8.59 (d, J=8.5 Hz, 1H), 8.25 (d, J=8.5 Hz, 1H), 3.94 (s,3H).

Methyl 6-bromo-4-cyclopropoxyquinoline-2-carboxylate

Step 1. 6-Bromo-4-cyclopropoxyquinoline

To 6-bromoquinolin-4-ol (0.63 g, 2.8 mmol), KI (0.23 g, 1.4 mmol) andCs₂CO₃ (1.6 g, 5.0 mmol) in DMF (7.0 mL) was added bromocyclopropane(0.42 mL, 5.6 mmol), the reaction flask was sealed and heated undermicrowave irradiation at 180° C. for 5 h. The reaction mixture wasdiluted with water, extracted with ethyl acetate (3×60 mL), the extractswere combined and concentrated to dryness in vacuo. The residue waspurified by flash chromatography (40 g silica gel column, solid loading,0-60% EtOAc/hexanes) to give 6-bromo-4-cyclopropoxyquinoline (0.31 g,1.2 mmol, 42% yield) as an tan solid. MS (ESI) m/z: 264.0 [M+H]⁺; ¹H NMR(400 MHz, CDCl₃) δ 8.76 (d, J=5.06 Hz, 1H), 8.27 (d, J=2.20 Hz, 1H),7.89 (d, J=9.02 Hz, 1H), 7.74 (dd, J=2.31, 8.91 Hz, 1H), 7.12 (d, J=5.06Hz, 1H), 3.94-3.99 (m, 1H), 0.91-0.97 (m, 4H).

Step 2. 6-Bromo-4-cyclopropoxyquinoline 1-oxide

To 6-bromo-4-cyclopropoxyquinoline (0.31 g, 1.2 mmol) in CH₂Cl₂ (8 mL)was added 3-chloroperoxybenzoic acid (0.47 g, 2.1 mmol), the resultingsolution was stirred at room temperature overnight. The solid wasremoved via suction filtration and the filtrate was concentrated todryness in vacuo. The residue was purified by flash chromatography (24 gsilica gel column, 0-10% MeOH/CH₂Cl₂) to give6-bromo-4-cyclopropoxyquinoline 1-oxide (0.32 g, 1.2 mmol, 98% yield) asan off-white solid. MS (ESI) m/z: 280.0 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃)δ 8.57-8.64 (m, 1H), 8.41-8.50 (m, 1H), 8.28 (d, J=1.98 Hz, 1H), 7.85(dd, J=2.20, 9.24 Hz, 1H), 7.01-7.06 (m, 1H), 3.93-3.99 (m, 1H),0.92-0.99 (m, 4H).

Step 3. 6-Bromo-4-cyclopropoxyquinoline-2-carbonitrile

A solution of 6-bromo-4-cyclopropoxyquinoline 1-oxide (0.32 g, 1.2 mmol)in acetonitrile (2.2 mL) was added to a solution of KCN (0.15 g, 2.3mmol) in MeOH (1.1 mL), stirred for 15 min, followed by dropwiseaddition of benzoyl chloride (0.27 mL, 2.3 mmol). The resulting mixturewas stirred at room temperature overnight. The reaction mixture wasconcentrated to dryness in vacuo, and the crude solid was purified byflash chromatography (40 g silica gel column, solid loading, 0-20%EtOAc/hexanes) to give 6-bromo-4-cyclopropoxyquinoline-2-carbonitrile(0.27 g, 0.93 mmol, 80% yield) as an off white solid. MS (ESI) m/z:289.1 [M+H]⁺; ¹H NMR (500 MHz, Chloroform-d) δ 8.29 (d, J=1.93 Hz, 1H),7.93 (d, J=9.08 Hz, 1H), 7.85 (dd, J=2.20, 9.08 Hz, 1H), 7.43 (s, 1H),4.00-4.05 (m, 1H), 1.01-1.05 (m, 2H), 0.98 (dd, J=1.79, 3.16 Hz, 2H).

Step 4. 6-Bromo-4-cyclopropoxyquinoline-2-carboxylic acid

To 6-bromo-4-cyclopropoxyquinoline-2-carbonitrile (0.3 g, 1.0 mmol) in2-propanol (10 mL) was added KOH (6M) (0.85 m, 5.1 mmol). The reactionmixture was heated at 80° C. overnight. The reaction mixture was cooledto room temperature and water (20 mL) and ethyl acetate (50 mL) wereadded. The precipitating product,6-bromo-4-cyclopropoxyquinoline-2-carboxylic acid (0.26 g, 0.83 mmol,81% yield) was collected as a white solid. MS (ESI) m/z: 308.0 [M+H]⁺;¹H NMR (500 MHz, Methanol-d₄) δ 8.19-8.23 (m, 1H), 7.98 (d, J=9.08 Hz,1H), 7.90 (s, 1H), 7.79 (dd, J=2.06, 8.94 Hz, 1H), 4.12-4.17 (m, 1H),0.99 (br d, J=6.05 Hz, 2H), 0.91 (br s, 2H).

Step 5. Methyl 6-bromo-4-cyclopropoxyquinoline-2-carboxylate

To 6-bromo-4-cyclopropoxyquinoline-2-carboxylic acid (0.36 g, 1.2 mmol)and K₂CO₃ (0.32 g, 2.3 mmol) in DMF (7 mL) was added iodomethane (1.8mL, 3.5 mmol). The reaction mixture was stirred at room temperature for15 min. The reaction mixture was diluted with ethyl acetate, and washedwith saturated aqueous NH₄Cl and brine solution. The organic layer wasdried over anhydrous MgSO₄ and concentrated under vacuum. The residuewas purified by flash chromatography (40 g silica gel column, 0-30%EtOAc/hexanes) to afford methyl6-bromo-4-cyclopropoxyquinoline-2-carboxylate (252 mg, 0.782 mmol, 67.0%yield) as an off-white solid. MS (ESI) m/z: 322.0 [M+H]⁺; ¹H NMR (500MHz, CDCl₃) δ 8.27 (d, J=2.20 Hz, 1H), 8.05 (d, J=9.08 Hz, 1H), 7.90 (s,1H), 7.79 (dd, J=2.20, 9.08 Hz, 1H), 4.07 (s, 3H), 4.02-4.06 (m, 1H),0.98 (s, 2H), 0.94 (br s, 2H).

Methyl 6-bromo-4-(methoxymethyl)quinoline-2-carboxylate

Step 1. Methyl 6-bromo-4-cyclopropoxyquinoline-2-carboxylate

To a mixture of methyl 6-bromoquinoline-2-carboxylate (0.52 g, 2.0mmol), iron(II) sulfate heptahydrate (0.16 g, 0.59 mmol) and iron (0.11g, 2.0 mmol) in MeOH (3 mL) and H₂O (2 mL) at 0° C. was added H2SO₄(0.10 mL, 2.0 mmol), followed by dropwise addition of H₂O₂ (50%) (0.40mL, 11.7 mmol). The reaction mixture was allowed to warm to roomtemperature and stirred for 4 h. The mixture was diluted with water,basified with NH₄OH, and extracted with EtOAc (2×100 mL). The combinedextracts were washed with brine, dried over anhydrous MgSO₄ andconcentrated in vacuo. The residue was purified by flash chromatography(40 g silica gel column, 0-100% EtOAc/hexanes) to afford methyl6-bromo-4-(hydroxymethyl)quinoline-2-carboxylate (0.29 g, 0.97 mmol, 49%yield) as a tan solid. MS (ESI) m/z: 296.0 [M+H]⁺; ¹H NMR (400 MHz,CDCl₃) δ 8.30-8.35 (m, 1H), 8.19 (dd, J=3.19, 5.39 Hz, 2H), 7.86 (dd,J=2.09, 9.13 Hz, 1H), 5.22 (s, 2H), 4.09 (s, 3H).

Step 2. Methyl 6-bromo-4-cyclopropoxyquinoline-2-carboxylate

To methyl 6-bromo-4-(hydroxymethyl)quinoline-2-carboxylate (0.29 g, 0.97mmol) in DMF (6.4 mL) was added NaH (60% in mineral oil) (0.08 g, 1.9mmol) portionwise. The reaction mixture was stirred at room temperaturefor 30 min, followed by addition of iodomethane (0.18 mL, 2.9 mmol). Thereaction mixture was stirred at room temperature for 5 h and thendiluted with ethyl acetate (50 mL), washed with water and brine, driedover anhydrous MgSO₄, filtered and concentrated under vacuum. Theresidue was purified by flash chromatography (24 g silica gel, 0-30%EtOAc/hexanes) to give methyl6-bromo-4-(methoxymethyl)quinoline-2-carboxylate (71 mg, 0.23 mmol, 24%yield) as a light yellow solid. MS (ESI) m/z: 310.0 [M+H]⁺; ¹H NMR (400MHz, CDCl₃) δ 8.25-8.27 (m, 1H), 8.17-8.22 (m, 2H), 7.86 (dd, J=2.20,9.02 Hz, 1H), 4.92 (d, J=0.88 Hz, 2H), 4.09 (s, 3H), 3.54 (s, 3H).

Methyl 3-(6-chloropyridin-3-yl)-5-(trifluoromethyl)benzoate

A mixture of (6-chloropyridin-3-yl)boronic acid (0.14 g, 0.89 mmol),methyl 3-bromo-5-(trifluoromethyl)benzoate (0.24 g, 0.85 mmol) andpotassium phosphate tribasic (2M aqueous solution) (0.85 mL, 1.7 mmol)in dioxane (3.5 mL) was added PdCl₂(dppf)-CH₂Cl₂ adduct (41.5 mg, 0.051mmol), the reaction was degassed and heated at 75° C. overnight. Theorganic layer was separated and concentrated. The residue was purifiedby flash chromatography (12 g silica gel, 0-30% ethyl acetate/hexanes)to afford methyl 3-(6-chloropyridin-3-yl)-5-(trifluoromethyl)benzoate(0.22 g, 0.70 mmol, 82% yield) as a white solid. MS (ESI) m/z: 316.0[M+H]⁺; ¹H NMR (500 MHz, CDCl₃) δ 8.65 (d, J=2.75 Hz, 1H), 8.41 (s, 1H),8.34 (s, 1H), 7.97 (s, 1H), 7.91 (dd, J=2.48, 8.25 Hz, 1H), 7.47 (d,J=8.25 Hz, 1H), 4.00 (s, 3H).

Methyl 3-(6-chloropyridin-3-yl)-5-fluorobenzoate

Methyl 3-(6-chloropyridin-3-yl)-5-fluorobenzoate was prepared followingthe procedure described for the preparation of methyl3-(6-chloropyridin-3-yl)-5-(trifluoromethyl)benzoate with replacement ofmethyl 3-bromo-5-(trifluoromethyl)benzoate with methyl3-bromo-5-fluorobenzoate (76% yield). MS (ESI) m/z: 265.9 [M+H]⁺; ¹H NMR(400 MHz, CDCl₃) δ 8.65-8.61 (m, 1H), 8.04 (t, J=1.4 Hz, 1H), 7.87 (dd,J=8.3, 2.5 Hz, 1H), 7.82-7.73 (m, 1H), 7.49-7.42 (m, 2H), 3.98 (s, 3H).

Methyl 3-(5-chloropyridin-2-yl)-5-(trifluoromethyl)benzoate

Methyl 3-(5-chloropyridin-2-yl)-5-(trifluoromethyl)benzoate was preparedfollowing the procedure described for the preparation of methyl3-(6-chloropyridin-3-yl)-5-(trifluoromethyl)benzoate with replacement of(6-chloropyridin-3-yl)boronic acid with (5-chloropyridin-2-yl)boronicacid (11% yield). MS (ESI) m/z: 315.9 [M+H]⁺; ¹H NMR (500 MHz,Chloroform-d) δ 8.79 (s, 1H), 8.69 (t, J=1.5 Hz, 1H), 8.51 (s, 1H), 8.35(s, 1H), 7.80 (d, J=1.7 Hz, 2H), 4.03-3.99 (m, 3H).

TABLE 1 Ex. Meth- No. Structure LCMS, FXR EC₅₀ (nM) & NMR od 1

MS (ESI) m/z: 484.3 [M + H]⁺; EC₅₀ = 14; ¹H NMR (500 MHz, DMSO-d₆) δ8.57 (d, J = 2.3 Hz, 1H), 7.88 (dd, J = 2.4, 9.1 Hz, 1H), 7.64 (d, J =8.0 Hz, 2H), 7.57 (dd, J = 7.0, 9.0 Hz, 1H), 6.79 (d, J = 9.2 Hz, 1H),6.15 (d, J = 16.3 Hz, 1H), 5.30 (dd, J = 7.0, 16.2 Hz, 1H), 4.28 (d, J =13.3 Hz, 2H), 2.93 (t, J = 12.4 Hz, 2H), 2.33 (dq, J = 4.3, 5.0, 8.5 Hz,1H), 1.60 (d, J = 12.9 Hz, 2H), 1.23-0.99 (m, 6H). A1 2

MS (ESI) m/z: 536.1 [M + H]⁺; EC₅₀ = 5; ¹H NMR (500 MHz, DMSO-d₆) δ7.84-7.76 (m, 2H), 7.68 (d, J = 8.0 Hz, 2H), 7.60 (dd, J = 7.1, 9.1 Hz,1H), 6.97-6.85 (m, 2H), 6.20 (d, J = 16.2 Hz, 1H), 5.37 (dd, J = 7.0,16.2 Hz, 1H), 3.76 (s, 3H), 3.56 (d, J = 12.0 Hz, 2H), 2.68 (t, J = 11.5Hz, 2H), 2.37 (q, J = 3.4, 5.5 Hz, 1H), 2.15 (br s, 1H), 1.67 (d, J =12.7 Hz, 2H), 1.39-0.97 (m, 6H). A2 3

MS (ESI) m/z: 484.3 [M + H]⁺; EC₅₀ = 107; ¹H NMR (500 MHz, DMSO-d6) δ8.57 (d, J = 2.4 Hz, 1H), 7.88 (dd, J = 2.4, 9.2 Hz, 1H), 7.65 (d, J =8.1 Hz, 2H), 7.57 (dd, J = 7.3, 9.0 Hz, 1H), 6.80 (d, J = 9.2 Hz, 1H),5.87 (d, J = 11.1 Hz, 1H), 5.55 (t, J = 10.8 Hz, 1H), 4.34 (d, J = 13.3Hz, 2H), 2.76 (q, J = 9.3, 11.8 Hz, 2H), 2.34 (d, J = 9.9 Hz, 1H), 2.09(td, J = 5.6, 9.9, 11.2 Hz, 1H), 1.28-1.00 (m, 8H). A1 4

MS (ESI) m/z: 572.3 [M + H]⁺; EC₅₀ = 2055; ¹H NMR (500 MHz, DMSO-d₆) δ8.24-8.06 (m, 1H), 7.61-7.59 (m, 1H), 7.59-7.56 (m, 2H), 7.55-7.50 (m,1H), 5.67 (s, 1H), 4.08 (br d, J = 10.6 Hz, 2H), 3.23 (br s, 2H),2.35-2.26 (m, 1H), 2.04-1.95 (m, 1H), 1.70 (br d, J = 12.6 Hz, 2H), 1.54(s, 3H), 1.51-1.41 (m, 2H), 1.15-1.09 (m, 2H), 1.07-1.02 (m, 2H). A1 5

MS (ESI) m/z: 548.4 [M + H]⁺; EC₅₀ = 1250; ¹H NMR (500 MHz, DMSO-d₆) δ7.66-7.48 (m, 5H), 7.25-6.93 (m, 3H), 5.62-5.58 (m, 1H), 4.36-4.14 (m,2H), 4.03-3.85 (m, 2H), 2.56 (br s, 2H), 2.19- 2.11 (m, 1H), 2.00-1.96(m, 1H), 1.59-1.54 (m, 2H), 1.50 (br s, 3H), 1.11 (br d, J = 5.5 Hz,2H), 1.03 (br d, J = 1.3 Hz, 2H). A2 6

MS (ESI) m/z: 572.0 [M + H]⁺; EC₅₀ = 536; ¹H NMR (500 MHz, DMSO-d₆) δ8.19 (br s, 1H), 7.65 (s, 1H), 7.64 (s, 1H), 7.61-7.52 (m, 2H), 6.27 (d,J = 16.8 Hz, 1H), 5.32 (d, J = 16.8 Hz, 1H), 3.74-3.56 (m, 1H),3.29-3.20 (m, 1H), 3.16 (s, 1H), 2.45-2.35 (m, 1H), 1.56-1.50 (m, 2H),1.49-1.41 (m, 2H), 1.22 (s, 1H), 1.19-1.14 (m, 2H), 1.09 (br d, J = 3.1Hz, 2H), 0.97 (s, 3H). A1 7

MS (ESI) m/z: 548.0 [M + H]⁺; EC₅₀ = 227; ¹H NMR (500 MHz, DMSO-d₆) δ8.24 (br d, J = 8.5 Hz, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.93 (br d, J =9.5 Hz, 1H), 7.65 (br d, J = 7.3 Hz, 1H), 7.61 (s, 1H), 7.59 (s, 1H),7.53-7.45 (m, 1H), 7.15 (br d, J = 2.1 Hz, 1H), 6.30-6.29 (m, 1H), 6.26(d, J = 16.5 Hz, 1H), 5.38 (d, J = 16.8 Hz, 1H), 2.94 (br t, J = 8.9 Hz,2H), 2.44-2.34 (m, 1H), 1.58-1.41 (m, 4H), 1.23 (s, 2H), 1.16 (br d, J =7.9 Hz, 2H), 1.09 (br d, J = 2.4 Hz, 2H), 0.99 (s, 3H). A2 8

MS (ESI) m/z: 556.2 [M + H]⁺; EC₅₀ = 120; ¹H NMR (500 MHz, DMSO-d₆) δ8.21 (d, J = 1.4 Hz, 1H), 7.66 (d, J = 1.4 Hz, 1H), 7.65 (s, 1H), 7.60(d, J = 6.9 Hz, 1H), 7.58 (d, J = 7.2 Hz, 1H), 6.13 (d, J = 16.0 Hz,1H), 5.19 (dd, J = 16.2, 8.8 Hz, 1H), 3.80-3.63 (m, 4H), 2.38-2.30 (m,1H), 1.75 (br s, 2H), 1.47-1.37 (m, 1H), 1.20-1.12 (m, 2H), 1.11- 1.03(m, 2H). A1 9

MS (ESI) m/z: 531.9 [M + H]⁺; EC₅₀ = 39; ¹H NMR (500 MHz, DMSO-d₆) δ8.13 (d, J = 8.5 Hz, 1H), 7.92 (d, J = 3.6 Hz, 1H), 7.90 (d, J = 4.1 Hz,1H), 7.67 (d, J = 1.4 Hz, 1H), 7.66 (s, 1H), 7.62-7.57 (m, 1H), 7.32(dd, J = 9.4, 2.5 Hz, 1H), 6.78 (d, J = 2.5 Hz, 1H), 6.15 (d, J = 16.2Hz, 1H), 5.16 (dd, J = 16.1, 8.9 Hz, 1H), 3.69 (d, J = 9.9 Hz, 2H),3.58-3.53 (m, 2H), 3.16 (br d, J = 5.5 Hz, 2H), 2.38-2.32 (m, 1H),1.47-1.35 (m, 1H), 1.22-1.13 (m, 2H), 1.11-1.05 (m, 2H). A2 10

MS (ESI) m/z: 558.2 [M + H]⁺; EC₅₀ = 64; ¹H NMR (500 MHz, DMSO-d6) δ8.15 (s, 1H), 7.74-7.79 (m, 2H), 7.69 (br d, J = 7.63 Hz, 1H), 7.57 (brd, J = 11.29 Hz, 1H), 6.12 (d, J = 16.17 Hz, 1H), 5.96- 6.03 (m, 1H),4.00 (br d, J = 10.07 Hz, 1H), 3.22 (br t, J = 11.90 Hz, 2H), 2.04 (brs, 1H), 1.71 (br d, J = 11.29 Hz, 2H), 1.24-1.37 (m, 2H), 1.01 (br d, J= 5.80 Hz, 2H), 0.86-0.93 (m, 2H) additional signals were lost due towater suppression. A1 11

MS (ESI) m/z: 482.8 [M + H]⁺; EC₅₀ = 148; ¹H NMR (500 MHz, DMSO-d₆) δ8.50-8.58 (m, 1H), 7.83 (br s, 1H), 7.64 (s, 2H), 7.56 (br d, J = 8.24Hz, 1H), 7.40 (s, 1H), 6.77 (br d, J = 9.16 Hz, 1H), 5.94-6.03 (m, 1H),5.90 (br d, J = 7.02 Hz, 1H), 4.30 (br d, J = 12.51 Hz, 2H), 4.23 (br d,J = 7.02 Hz, 1H), 2.83- 2.94 (m, 2H), 1.72 (br s, 1H), 1.59 (br d, J =12.51 Hz, 2H), 1.12 (br d, J = 9.46 Hz, 2H), 0.85 (br d, J = 6.71 Hz,2H), 0.54 (br d, J = 3.97 Hz, 2H). A1 12

MS (ESI) m/z: 557.2 [M + H]⁺; EC₅₀ = 226; ¹H NMR (500 MHz, DMSO-d₆) δ8.18 (s, 1H), 7.58 (br d, J = 11.60 Hz, 1H), 7.53 (s, 2H), 7.40 (d, J =7.93 Hz, 1H), 7.31 (s, 1H), 6.54 (d, J = 16.48 Hz, 1H), 5.51 (dd, J =7.02, 16.17 Hz, 1H), 3.99 (br d, J = 10.68 Hz, 2H), 3.63-3.73 (m, 1H),3.26 (br t, J = 11.60 Hz, 2H), 2.41 (br d, J = 7.63 Hz, 1H), 1.72 (br d,J = 11.60 Hz, 2H), 1.26 (br s, 2H), 1.07 (br s, 2H), 0.99 (d, J = 6.41Hz, 2H). A1 13

MS (ESI) m/z: 484.3 [M + H]⁺; EC₅₀ = 206; ¹H NMR (500 MHz, DMSO-d₆) δ7.74-7.51 (m, 4H), 7.23 (d, J = 7.3 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H),6.16 (d, J = 16.2 Hz, 1H), 5.33 (dd, J = 7.0, 16.4 Hz, 1H), 4.26 (d, J =13.2 Hz, 2H), 2.84 (t, J = 12.3 Hz, 2H), 2.40-2.31 (m, 1H), 2.26 (br s,1H), 1.60 (d, J = 12.8 Hz, 2H), 1.24-1.00 (m, 6H). A1 14

MS (ESI) m/z: 558.3 [M + H]⁺; EC₅₀ = 11; Mouse in vivo (30 mg/kg, @ 6h): Cyp7a1 = −96%, FgF15 =+ 10x; ¹H NMR (500 MHz, DMSO-d₆) δ 8.20 (s,1H), 7.66 (d, J = 7.9 Hz, 2H), 7.62-7.56 (m, 2H), 6.19 (d, J = 16.2 Hz,1H), 5.35 (dd, J = 6.9, 16.3 Hz, 1H), 3.97 (br s, 2H), 3.24 (t, J = 12.6Hz, 2H), 2.36 (td, J = 4.4, 8.6 Hz, 2H), 1.70 (d, J = 12.9 Hz, 2H),1.35-1.01 (m, 6H). A1 15

MS (ESI) m/z: 558.1 [M + H]⁺; EC₅₀ = 130; ¹H NMR (500 MHz, DMSO-d₆) δ8.19 (s, 1H), 7.67 (d, J = 8.1 Hz, 2H), 7.62-7.55 (m, 2H), 5.89 (d, J =11.1 Hz, 1H), 5.59 (t, J = 10.8 Hz, 1H), 4.01 (br s, 2H), 3.10 (t, J =12.4 Hz, 2H), 2.44-2.33 (m, 1H), 2.14-2.06 (m, 1H), 1.42-1.21 (m, 4H),1.22-1.08 (m, 4H). A1 16

MS (ESI) m/z: 484.1 [M + H]⁺; EC₅₀ = 109; ¹H NMR (500 MHz, DMSO-d₆) δ8.55 (s, 1H), 7.87 (br d, J = 8.54 Hz, 1H), 7.72-7.79 (m, 2H), 7.67 (brt, J = 8.09 Hz, 1H), 6.79 (br d, J = 9.16 Hz, 1H), 6.09 (br d, J = 16.48Hz, 1H), 5.94 (br dd, J = 6.87, 16.02 Hz, 1H), 4.30 (br d, J = 12.51 Hz,2H), 2.92 (br t, J = 12.21 Hz, 2H), 2.02 (br d, J = 3.97 Hz, 1H), 1.63(br d, J = 12.21 Hz, 2H), 1.14 (br d, J = 10.38 Hz, 2H), 0.96-1.04 (m,3H), 0.88 (br d, J = 2.75 Hz, 2H). A1 17

MS (ESI) m/z: 584.1 [M + H]⁺; EC₅₀ = 243; ¹H NMR (500 MHz, DMSO-d₆) δ8.20 (d, J = 1.5 Hz, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.61-7.54 (m, 2H),5.72 (d, J = 11.0 Hz, 1H), 5.50 (t, J = 10.4 Hz, 1H), 4.34 (br s, 1H),2.87-2.75 (m, 1H), 2.12-2.02 (m, 3H), 1.72 (d, J = 7.9 Hz, 1H), 1.61 (t,J = 12.3 Hz, 1H), 1.41 (d, J = 13.1 Hz, 1H), 1.28-1.10 (m, 4H),additional signals missing due to water signal suppression. A1 18

MS (ESI) m/z: 485.2 [M + H]⁺; EC₅₀ = 447; ¹H NMR (500 MHz, DMSO-d₆) δ7.79 (d, J = 9.6 Hz, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.58 (dd, J = 7.0,9.0 Hz, 1H), 7.25 (d, J = 9.6 Hz, 1H), 6.18 (d, J = 16.2 Hz, 1H), 5.33(dd, J = 6.9, 16.3 Hz, 1H), 4.39 (d, J = 13.2 Hz, 2H), 3.05 (t, J = 12.5Hz, 2H), 2.42-2.25 (m, 2H), 1.66 (d, J = 13.0 Hz, 2H), 1.31-0.94 (m,6H). A1 19

MS (ESI) m/z: 538.1 [M + H]⁺; EC₅₀ = 194; ¹H NMR (500 MHz, DMSO-d₆) δ8.79 (s, 1H), 7.83 (s, 1H), 7.66 (d, J = 8.2 Hz, 2H), 7.58 (dd, J = 7.1,9.0 Hz, 1H), 6.18 (d, J = 16.3 Hz, 1H), 5.34 (dd, J = 6.9, 16.2 Hz, 1H),4.60 (d, J = 13.1 Hz, 2H), 3.66 (s, 3H), 2.93 (t, J = 12.4 Hz, 2H),2.42-2.22 (m, 2H), 1.62 (d, J = 12.8 Hz, 2H), 1.21-0.97 (m, 6H). A1 20

MS (ESI) m/z: 537.1 [M + H]⁺; EC₅₀ = 21; ¹H NMR (500 MHz, DMSO-d₆) δ8.02 (d, J = 8.8 Hz, 1H), 7.79 (s, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.58(t, J = 8.1 Hz, 1H), 6.77 (d, J = 8.7 Hz, 1H), 6.18 (d, J = 16.2 Hz,1H), 5.35 (dd, J = 6.9, 16.2 Hz, 1H), 4.23 (d, J = 13.0 Hz, 2H), 3.70(s, 3H), 2.86 (t, J = 12.2 Hz, 2H), 2.36 (br d, J = 5.5 Hz, 1H), 2.26(br s, 1H), 1.63 (d, J = 12.7 Hz, 2H), 1.21-0.94 (m, 6H). A2 21

MS (ESI) m/z: 502.0 [M + H]⁺; EC₅₀ = 20; ¹H NMR (500 MHz, DMSO-d₆) δ8.48 (s, 1H), 7.87-7.47 (m, 4H), 6.15 (d, J = 16.2 Hz, 1H), 5.39 (dd, J= 6.8, 16.3 Hz, 1H), 4.16 (d, J = 13.2 Hz, 2H), 3.02 (dd, J = 10.6, 23.1Hz, 2H), 2.41-2.23 (m, 2H), 1.66 (d, J = 13.2 Hz, 2H), 1.33-1.0 (m, 6H).A1 22

MS (ESI) m/z: 540.0 [M + H]⁺; EC₅₀ = 12; ¹H NMR (500 MHz, DMSO-d₆) δ8.32 (s, 1H), 7.86 (s, 1H), 7.65 (d, J = 8.6 Hz, 2H), 7.62-7.56 (m, 1H),7.45 (s, 1H), 6.18 (d, J = 16.3 Hz, 1H), 5.41 (dd, J = 6.8, 16.3 Hz,1H), 3.98 (d, J = 13.2 Hz, 2H), 2.44-2.28 (m, 2H), 1.72 (d, J = 13.2 Hz,2H), 1.32-1.03 (m, 6H), additional signals missing due to water signalsuppression. A1 23

MS (ESI) m/z: 524.3 [M + H]⁺; EC₅₀ = 156; ¹H NMR (500 MHz, DMSO-d₆) δ7.77 (s, 1H), 7.71- 7.62 (m, 3H), 7.58 (dd, J = 6.9, 9.1 Hz, 1H), 7.44(d, J = 8.3 Hz, 1H), 6.17 (d, J = 16.2 Hz, 1H), 5.41 (dd, J = 6.8, 16.3Hz, 1H), 4.06 (d, J = 13.0 Hz, 2H), 2.41-2.25 (m, 2H), 1.69 (d, J = 13.1Hz, 2H), 1.32-1.21 (m, 2H), 1.17 (dt, J = 3.2, 8.2 Hz, 2H), 1.09 (dt, J= 3.2, 5.5 Hz, 2H), additional signals missing due to water signalsuppression. A1 24

MS (ESI) m/z: 485.1 [M + H]⁺; EC₅₀ = 127; ¹H NMR (500 MHz, DMSO-d₆) δ8.61 (s, 1H), 8.31 (s, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.59 (dd, J = 7.1,9.0 Hz, 1H), 6.18 (d, J = 16.3 Hz, 1H), 5.33 (dd, J = 6.9, 16.3 Hz, 1H),4.37 (d, J = 13.4 Hz, 2H), 3.01 (t, J = 12.5 Hz, 2H), 2.41-2.30 (m, 2H),1.65 (d, J = 13.0 Hz, 2H), 1.21-1.03 (m, 6H). A1 25

MS (ESI) m/z: 485.2 [M + H]⁺; EC₅₀ = 83; ¹H NMR (500 MHz, DMSO-d₆) δ8.73 (s, 2H), 7.66 (d, J = 8.0 Hz, 2H), 7.59 (dd, J = 7.1, 9.0 Hz, 1H),6.18 (d, J = 16.2 Hz, 1H), 5.33 (dd, J = 6.9, 16.2 Hz, 1H), 4.61 (d, J =13.3 Hz, 2H), 3.02 (t, J = 12.4 Hz, 2H), 2.41-2.30 (m, 2H), 1.64 (d, J =13.0 Hz, 2H), 1.21-1.02 (m, 6H). A1 26

MS (ESI) m/z: 534.1 [M + H]⁺; EC₅₀ = 6; ¹H NMR (500 MHz, DMSO-d₆) δ 8.21(d, J = 8.6 Hz, 1H), 7.95 (dd, J = 8.9, 17.0 Hz, 2H), 7.67 (d, J = 8.1Hz, 3H), 7.59 (dd, J = 7.2, 9.0 Hz, 1H), 7.19 (d, J = 2.8 Hz, 1H), 6.20(d, J = 16.2 Hz, 1H), 5.36 (dd, J = 6.9, 16.3 Hz, 1H), 3.86 (d, J = 12.7Hz, 2H), 2.89 (t, J = 12.1 Hz, 2H), 2.42-2.32 (m, 1H), 2.26 (br. s, 1H),1.68 (d, J = 12.9 Hz, 2H), 1.34-1.02 (m, 6H). A2 27

MS (ESI) m/z: 485.0 [M + H]⁺; EC₅₀ = 2326; ¹H NMR (500 MHz, DMSO-d₆) δ8.48 (s, 2H), 7.65 (d, J = 8.1 Hz, 2H), 7.58 (t, J = 8.2 Hz, 1H), 6.18(d, J = 16.4 Hz, 1H), 5.34 (dd, J = 6.8, 16.2 Hz, 1H), 3.89 (d, J = 12.5Hz, 2H), 2.92 (t, J = 12.3 Hz, 2H), 2.35 (br s, 1H), 2.28 (br s, 1H),1.64 (d, J = 13.1 Hz, 2H), 1.31-1.05 (m, 6H). A2 28

MS (ESI) m/z: 537.0 [M + H]⁺; EC₅₀ = 500; ¹H NMR (500 MHz, DMSO-d₆) δ7.94 (s, 1H), 7.74 (d, J = 8.3 Hz, 1H), 7.68 (d, J = 8.1 Hz, 2H), 7.61(dd, J = 7.1, 9.0 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 6.22 (d, J = 16.2Hz, 1H), 5.39 (dd, J = 6.8, 16.2 Hz, 1H), 3.59 (s, 3H), 3.53 (d, J =12.4 Hz, 2H), 2.92 (t, J = 12.1 Hz, 2H), 2.42-2.33 (m, 1H), 2.24 (br s,1H), 1.67 (d, J = 12.9 Hz, 2H), 1.45-1.30 (m, 2H), 1.22-1.04 (m, 4H). A129

MS (ESI) m/z: 524.2 [M + H]⁺; EC₅₀ = 60; ¹H NMR (500 MHz, DMSO-d₆) δ9.17 (s, 1H), 7.67-7.63 (m, 3H), 7.58 (dd, J = 7.0, 9.0 Hz, 1H), 7.08(d, J = 2.7 Hz, 1H), 6.16 (d, J = 16.1 Hz, 1H), 5.34 (dd, J = 6.9, 16.2Hz, 1H), 4.33 (d, J = 13.2 Hz, 2H), 2.94 (t, J = 12.3 Hz, 2H), 2.40-2.24(m, 2H), 1.62 (d, J = 12.8 Hz, 2H), 1.22-1.03 (m, 6H). A1 30

MS (ESI) m/z: 484.1 [M + H]⁺; EC₅₀ = 78; ¹H NMR (500 MHz, DMSO-d₆) δ8.31 (d, J = 3.0 Hz, 1H), 7.83 (d, J = 8.9 Hz, 1H), 7.66 (d, J = 8.0 Hz,2H), 7.59 (dd, J = 7.0, 9.0 Hz, 1H), 7.30 (dd, J = 3.0, 9.2 Hz, 1H),6.18 (d, J = 16.3 Hz, 1H), 5.34 (dd, J = 7.0, 16.2 Hz, 1H), 3.84 (d, J =13.0 Hz, 2H), 2.89( t, J = 12.3 Hz, 2H), 2.40-2.33 (m, 1H), 2.27 (br s,1H), 1.64 (d, J = 13.4 Hz, 2H), 1.29-1.03 (m, 6H). A2 31

MS (ESI) m/z: 538.2 [M + H]⁺; EC₅₀ = 414; ¹H NMR (500 MHz, DMSO-d₆) δ8.78 (d, J = 1.7 Hz, 1H), 8.37 (d, J = 1.8 Hz, 1H), 7.67 (d, J = 7.7 Hz,2H), 7.60 (dd, J = 7.2, 8.9 Hz, 1H), 6.19 (d, J = 16.1 Hz, 1H), 5.36(dd, J = 6.9, 16.2 Hz, 1H), 4.35 (d, J = 12.4 Hz, 2H), 3.88 (s, 3H),2.88 (t, J = 12.1 Hz, 2H), 2.41-2.31 (m, 1H), 2.22 (br s, 1H), 1.65 (d,J = 12.8 Hz, 2H), 1.36-1.02 (m, 6H). A2 32

MS (ESI) m/z: 557.1 [M + H]⁺; EC₅₀ = 47; ¹H NMR (500 MHz, DMSO-d₆) δ8.09- 8.16 (m, 1H), 7.66 (d, J = 7.99 Hz, 2H), 7.53-7.60 (m, 2H), 7.43(s, 1H), 6.02 (d, J = 16.24 Hz, 1H), 5.88-5.97 (m, 1H), 3.78 (br s, 3H),3.17-3.26 (m, 2H), 1.72-1.78 (m, 1H), 1.65-1.71 (m, 2H), 1.26 (br d, J =9.34 Hz, 2H), 0.84-0.92 (m, 2H), 0.55 (br d, J = 4.46 Hz, 2H). A1 33

MS (ESI) m/z: 534.3 [M + H]⁺; EC₅₀ = 15; ¹H NMR (500 MHz, DMSO-d₆) δ8.33 (d, J = 2.0 Hz, 1H), 8.12 (d, J = 9.3 Hz, 1H), 7.98 (dd, J = 2.0,8.7 Hz, 1H), 7.66 (d, J = 8.6 Hz, 2H), 7.58 (dd, J = 7.2, 9.0 Hz, 1H),7.52 (d, J = 8.8 Hz, 1H), 7.27 (d, J = 9.3 Hz, 1H), 6.19 (d, J = 16.3Hz, 1H), 5.34 (dd, J = 6.9, 16.3 Hz, 1H), 4.49 (d, J = 13.3 Hz, 2H),3.07-2.95 (m, 2H), 2.41-2.29 (m, 2H), 1.66 (d, J = 11.9 Hz, 2H),1.21-1.03 (m, 6H). A2 34

MS (ESI) m/z: 498.2 [M + H]⁺; EC₅₀ = 403.3; ¹H NMR (500 MHz, DMSO-d₆) δ8.58 (br s, 1H), 7.88 (br d, J = 8.8 Hz, 1H), 7.63 (d, J = 8.1 Hz, 2H),7.58-7.51 (m, 1H), 6.77 (br d, J = 8.9 Hz, 1H), 6.24 (d, J = 16.7 Hz,1H), 5.34 (d, J = 16.7 Hz, 1H), 3.76 (br d, J = 13.1 Hz, 1H), 3.12 (brt, J = 10.0 Hz, 2H), 2.46-2.32 (m, 1H), 1.47-1.37 (m, 2H), 1.36-1.27 (m,2H), 1.22 (s, 1H), 1.20-1.14 (m, 2H), 1.10-1.05 (m, 2H), 0.95 (s, 3H).A1 35

MS (ESI) m/z: 536.2 [M + H]⁺; EC₅₀ = 25; ¹H NMR (500 MHz, DMSO-d₆) δ7.69- 7.63 (m, 2H), 7.59 (dd, J = 7.1, 9.2 Hz, 1H), 7.45 (d, J = 8.8 Hz,1H), 7.06 (s, 1H), 6.86 (dd, J = 2.1, 8.8 Hz, 1H), 6.80 (s, 1H), 6.18(d, J = 16.0 Hz, 1H), 5.42 (dd, J = 6.9, 16.3 Hz, 1H), 3.94 (s, 3H),3.63 (d, J = 12.1 Hz, 2H), 2.76 (t, J = 11.8 Hz, 2H), 2.41-2.29 (m, 1H),2.19 (br s, 1H), 1.68 (d, J = 12.2 Hz, 2H), 1.32 (q, J = 12.0, 12.8 Hz,2H), 1.18 (dq, J = 3.6, 4.1, 6.7 Hz, 2H), 1.09 (dd, J = 2.6, 5.2 Hz,2H). A2 36

MS (ESI) m/z: 484.2 [M + H]⁺; EC₅₀ = 144; ¹H NMR (500 MHz, CDCl₃) δ 8.26(d, J = 5.0 Hz, 1H), 7.43 (d, J = 1.1 Hz, 1H), 7.41 (s, 1H), 7.36-7.32(m, 1H), 7.21 (s, 1H), 7.09-7.05 (m, 1H), 6.07 (dd, J = 16.1, 1.0 Hz,1H), 5.45 (dd, J = 16.0, 7.2 Hz, 1H), 4.34-4.22 (m, 2H), 3.92 (s, 3H),2.91 (td, J = 12.7, 2.3 Hz, 2H), 2.30-2.21 (m, 1H), 2.11 (tt, J = 8.4,5.0 Hz, 1H), 1.73 (br dd, J = 13.2, 1.9 Hz, 2H), 1.16-1.11 (m, 2H),0.91-0.80 (m, 4H). A1 37

MS (ESI) m/z: 534.1 [M + H]⁺; EC₅₀ = 17; ¹H NMR (500 MHz, DMSO-d₆) δ9.08 (s, 1H), 8.38 (s, 1H), 7.93 (s, 1H), 7.64 (d, J = 8.0 Hz, 3H), 7.58(q, J = 8.3, 9.4 Hz, 1H), 7.36 (s, 1H), 6.18 (d, J = 16.2 Hz, 1H), 5.34(dd, J = 6.9, 16.2 Hz, 1H), 3.86 (d, J = 12.8 Hz, 2H), 2.90 (t, J = 12.2Hz, 2H), 2.42-2.22 (m, 2H), 1.67 (d, J = 12.6 Hz, 2H), 1.33-1.06 (m,6H). A2 38

MS (ESI) m/z: 601.9 [M + H]⁺; EC₅₀ = 5; ¹H NMR (500 MHz, DMSO-d₆) δ 8.20(s, 1H), 8.07 (d, J = 9.4 Hz, 1H), 7.83 (dd, J = 9.6, 1.9 Hz, 1H),7.65(s, 1H), 7.63 (s, 1H), 7.59-7.54 (m, 1H), 7.04 (br s, 1H), 6.18 (d,J = 15.7 Hz, 1H), 5.36 (dd, J = 16.2, 6.9 Hz, 1H), 3.89 (br d, J = 13.2Hz, 2H), 3.03-2.98 (m, 2H), 2.40-2.33 (m, 1H), 2.33-2.27 (m, 1H), 1.71(br d, J = 11.0 Hz, 2H), 1.31-1.21 (m, 2H), 1.19-1.13 (m, 2H), 1.10-1.06(m, 2H). A2 39

MS (ESI) m/z: 591.1 [M + H]⁺; EC₅₀ = 5; ¹H NMR (500 MHz, DMSO-d₆) δ 8.05(d, J = 10.0 Hz, 1H), 7.67 (d, J = 7.9 Hz, 2H), 7.60 (dd, J = 7.1, 9.0Hz, 1H), 7.55-7.50 (m, 1H), 7.48 (s, 1H), 6.21 (d, J = 16.2 Hz, 1H),5.38 (dd, J = 7.0, 16.2 Hz, 1H), 3.54 (d, J = 12.1 Hz, 2H), 2.73 (t, J =11.5 Hz, 2H), 2.42-2.33 (m, 1H), 2.20 (br s, 1H), 1.70 (d, J = 12.8 Hz,2H), 1.30 (q, J = 10.7 Hz, 2H), 1.18 (dt, J = 3.2, 8.3 Hz, 2H), 1.11(dt, J = 3.2, 5.5 Hz, 2H). A2 40

MS (ESI) m/z: 498.4 [M + H]⁺; EC₅₀ = 947; ¹H NMR (500 MHz, DMSO-d₆) δ7.97 (d, J = 5.0 Hz, 1H), 7.65 (d, J = 0.8 Hz, 1H), 7.64 (s, 1H),7.60-7.54 (m, 1H), 6.66 (s, 1H), 6.49 (d, J = 5.0 Hz, 1H), 6.15 (d, J =17.1 Hz, 1H), 5.32 (dd, J = 16.4, 7.0 Hz, 1H), 4.15-4.08 (m, 2H), 2.80(br t, J = 11.3 Hz, 2H), 2.37-2.30 (m, 1H), 2.28-2.18 (m, 1H), 1.91 (s,2H), 1.58 (br dd, J = 12.9, 1.9 Hz, 2H), 1.19-1.13 (m, 2H), 1.11-1.03(m, 4H). A1 41

MS (ESI) m/z: 537.3 [M + H]⁺; EC₅₀ = 236; ¹H NMR (500 MHz, DMSO-d₆) δ7.68 (dd, J = 4.1, 8.1 Hz, 2H), 7.64-7.53 (m, 2H), 7.39 (s, 1H), 7.25(d, J = 9.1 Hz, 1H), 6.21 (d, J =16.6 Hz, 1H), 5.37 (dd, J = 6.7, 16.2Hz, 1H), 4.06 (s, 3H), 2.67 (t, J = 11.7 Hz, 2H), 2.41-2.32 (m, 1H),2.17 (br s, 1H), 1.69 (br d, J = 12.7 Hz, 2H), 1.32 (br d, J = 12.1 Hz,2H), 1.18 (br d, J = 8.6 Hz, 2H), 1.10 (br s, 2H), additional signalsmissing due to water signal suppression. A2 42

MS (ESI) m/z: 500.3 [M + H]⁺; EC₅₀ = 512; ¹H NMR (500 MHz, DMSO-d₆) δ8.58 (d, J = 2.14 Hz, 1H), 7.83-7.91 (m, 1H), 7.67 (br s, 1H), 7.54 (brs, 3H), 6.83 (d, J = 9.16 Hz, 1H), 6.09 (d, J = 16.17 Hz, 1H), 5.58 (dd,J = 7.02, 16.17 Hz, 1H), 4.31-4.41 (m, 2H), 2.94 (br s, 2H), 2.30 (br s,2H), 1.61-1.70 (m, 2H), 1.10-1.21 (m, 4H), 1.02-1.07 (m, 2H). A1 43

MS (ESI) m/z: 574.1 [M + H]⁺; EC₅₀ = 42; ¹H NMR (500 MHz, DMSO-d₆) δ8.15 (s, 1H), 7.67 (br d, J = 2.14 1H), 7.51-7.60 (m, 4H), 6.07-6.15 (m,1H), 5.62 (br d, J = 7.02 Hz, 1H), 4.01 (br d, J = 11.90 Hz, 2H), 3.24(br s, 2H), 2.30 (br s, 2H), 1.73 (br d, J = 12.51 Hz, 2H), 1.24-1.36(m, 2H), 1.13 (br d, J = 8.24 Hz, 2H), 1.02-1.07 (m, 2H). A1 44

MS (ESI) m/z: 574.1 [M + H]⁺; EC₅₀ = 31; ¹H NMR (500 MHz, DMSO-d₆) δ8.15 (s, 1H), 7.67 (br d, J = 2.14 Hz, 1H), 7.51-7.60 (m, 4H), 6.07-6.15(m, 1H), 5.62 (br d, J = 7.02 Hz, 1H), 4.01 (br d, J = 11.90 Hz, 2H),3.24 (br s, 2H), 2.30 (br s, 2H), 1.73 (br d, J = 12.51 Hz, 2H),1.24-1.46 (m, 2H), 1.13 (br d, J = 8.24 Hz, 2H), 1.02-1.07 (m, 2H). A245

MS (ESI) m/z: 602.3 [M + H]⁺; EC₅₀ = 12; ¹H NMR (500 MHz, DMSO-d₆) δ8.23 (s, 1H), 8.03-8.10 (m, 1H), 7.93 (br d, J = 7.63 Hz, 1H), 7.74-7.85(m, 3H), 7.47-7.59 (m, 1H), 7.05 (br s, 1H), 6.11 (d, J = 16.17 Hz, 1H),5.40 (dd, J = 6.87, 16.33 Hz, 2H), 3.82- 3.93 (m, 2H), 2.95 (br t, J =11.44 Hz, 2H), 2.33 (br t, J = 5.04 Hz, 2H), 1.69 (br d, J = 12.51 Hz,2H), 1.27 (br d, J = 9.77 Hz, 2H), 1.14-1.20 (m, 2H), 1.07 (br d, J =3.05 Hz, 2H). A2 46

MS (ESI) m/z: 537.9 [M + H]⁺; EC₅₀ = 117; ¹H NMR (500 MHz, DMSO-d6) δ8.36 (d, J = 1.8 Hz, 1H), 7.85 (dd, J = 8.5, 1.8 Hz, 1H), 7.67 (d, J =8.0 Hz, 2H), 7.61 (dd, J = 9.0, 7.0 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H),6.16 (d, J = 16.1 Hz, 1H), 5.19 (dd, J = 16.1, 8.8 Hz, 1H), 3.81-3.71(two proton signals were lost due to water suppression), 3.66 (d, J =10.0 Hz, 2H), 2.35 (tt, J = 8.5, 5.1 Hz, 1H), 1.75 (s, 2H), 1.43 (dd, J= 8.8, 3.9 Hz, 1H), 1.27-1.04 (m, 4H). A1 47

MS (ESI) m/z: 481.2 [M + H]⁺; EC₅₀ = 40; ¹H NMR (500 MHz, DMSO-d6) δ7.72 (d, J = 8.7 Hz, 2H), 7.67 (d, J = 7.4 Hz, 2H), 7.60 (dd, J = 9.1,7.1 Hz, 1H), 6.53 (d, J = 8.6 Hz, 2H), 6.14 (d, J = 16.1 Hz, 1H), 5.14(dd, J = 16.0, 9.0 Hz, 1H), 3.56 (d, J = 10.1 Hz, 1H, one proton signalwas lost due to water suppression), 3.39-3.19 (m, 2H), 2.34 (td, J =8.5, 4.3 Hz, 1H), 1.71-1.65 (m, 2H), 1.38-1.30 (m, 1H), 1.21-0.98 (m,4H). A2 48

MS (ESI) m/z: 532.0 [M + H]⁺; EC₅₀ = 468; ¹H NMR (500 MHz, DMSO-d6) δ9.14 (s, 1H), 8.49 (s, 1H), 8.03 (d, J = 9.0 Hz, 1H), 7.68 (d, J = 7.9Hz, 2H), 7.61 (dd, J = 9.0, 7.0 Hz, 1H), 7.40 (d, J = 9.0 Hz, 1H), 7.09(s, 1H), 6.16 (d, J = 16.2 Hz, 1H), 5.18 9dd, J = 16.1, 8.9 Hz, 1H),3.72 (d, J = 10.1 Hz, 2H), 3.44 (d, J = 9.5 Hz, 1H, one proton signalwas lost due to water suppression), 2.45-2.23 (m, 1H), 1.80-1.72 (m,2H), 1.45-1.38 (m, 1H), 1.24-0.98 (m, 4H). A2 49

MS (ESI) m/z: 558.1 [M + H]⁺; EC₅₀ = 23; ¹H NMR (500 MHz, DMSO-d₆) δ8.21 (br s, 1H), 7.94 (br d, J = 7.32 Hz, 1H), 7.74-7.86 (m, 2H),7.55-7.66 (m, 1H), 7.52 (br d, J = 7.32 Hz, 1H), 6.11 (br d, J = 16.17Hz, 1H), 5.40 (br dd, J = 6.71, 16.17 Hz, 1H), 3.99 (br d, J = 9.16 Hz,2H), 3.16-3.28 (m, 1H), 2.26-2.40 (m, 3H), 1.69 (br d, J = 12.21 Hz,2H), 1.25 (br d, J = 10.07 Hz, 2H), 1.13-1.19 (m, 2H), 1.08 (br d, J =2.75 Hz, 2H). A1 50

MS (ESI) m/z: 464.1 [M + H]⁺; EC₅₀ = 671; ¹H NMR (400 MHz, CDCl₃) δ7.39-7.50 (m, 4H), 7.31-7.38 (m, 1H), 6.83 (d, J = 9.02 Hz, 2H), 6.08(dd, J = 1.21, 16.18 Hz, 1H), 5.44 (dd, J = 7.04, 16.07 Hz, 1H),3.72-3.80 (m, 2H), 2.81-2.94 (m, 2H), 2.18-2.28 (m, 1H), 2.07-2.14 (m,1H), 1.74 (br d, J = 10.56 Hz, 2H), 1.29-1.43 (m, 2H), 1.22-1.29 (m,2H), 1.10-1.18 (m, 2H). A2 51

MS (ESI) m/z: 464.1 [M + H]⁺; EC₅₀ = 11; ¹H NMR (400 MHz, CDCl₃) δ7.39-7.50 (m, 4H), 7.31-7.38 (m, 1H), 6.83 (d, J = 9.02 Hz, 2H), 6.08(dd, J = 1.21, 16.18 Hz, 1H), 5.44 (dd, J = 7.04, 16.07 Hz, 1H),3.72-3.80 (m, 2H), 2.81-2.94 (m, 2H), 2.18-2.28 (m, 1H), 2.07-2.14 (m,1H), 1.74 (br d, J = 10.56 Hz, 2H), 1.29-1.43 (m, 2H), 1.22-1.29 (m,2H), 1.10-1.18 (m, 2H). A2 52

MS (ESI) m/z: 600.1 [M + H]⁺; EC₅₀ = 77; ¹H NMR (400 MHz, DMSO-d₆) δ8.20-8.15 (m, 1H), 8.06 (d, J = 9.5 Hz, 1H), 7.68 (d, J = 1.8 Hz, 1H),7.66 (s, 1H), 7.62-7.59 (m, 1H), 7.48-7.43 (m, 1H), 6.69 (br s, 1H),6.13 (d, J = 16.0 Hz, 1H), 5.20 (dd, J = 16.1, 8.9 Hz, 1H), 3.72 (br d,J = 10.1 Hz, 2H), 3.49 (br d, J = 8.9 Hz, 2H), 2.34-2.31 (m, 1H), 1.78(br s, 2H), 1.45-1.38 (m, 1H), 1.18-1.13 (m, 2H), 1.12-1.03 (m, 2H). A253

MS (ESI) m/z: 516.9 [M + H]⁺; EC₅₀ = 23; ¹H NMR (500 MHz, DMSO-d₆) δ7.63-7.71 (m, 3H), 7.59 (br d, J = 7.32 Hz, 1H), 6.81-6.89 (m, 2H), 6.15(d, J = 16.48 Hz, 1H), 5.32 (dd, J = 6.87, 16.33 Hz, 1H), 3.75 (br d, J= 13.12 Hz, 2H), 2.83 (br s, 2H), 2.34 (br s, 1H), 2.24 (br s, 1H), 1.59(br d, J = 12.82 Hz, 2H), 1.15 (br d, J = 8.54 Hz, 4H), 1.07 (br d, J =2.7 Hz, 2H). A2 54

MS (ESI) m/z: 516.9 [M + H]⁺; EC₅₀ = 15; ¹H NMR (500 MHz, DMSO-d₆) δ7.63-7.71 (m, 3H), 7.59 (br d, J = 7.32 Hz, 1H), 6.81-6.89 (m, 2H), 6.15(d, J = 16.48 Hz, 1H), 5.32 (dd, J = 6.87, 16.33 Hz, 1H), 3.75 (br d, J= 13.12 Hz, 2H), 2.83 (br s, 2H), 2.34 (br s, 1H), 2.24 (br s, 1H), 1.59(br d, J = 12.82 Hz, 2H), 1.15 (br d, J = 8.54 Hz, 4H), 1.07 (br d, J =2.75 Hz, 2H). A2 55

MS (ESI) m/z: 516.9 [M + H]⁺; EC₅₀ = 90; ¹H NMR (500 MHz, DMSO-d₆) δ7.63- 7.71 (m, 3H), 7.59 (br d, J = 7.32 Hz, 1H), 6.81-6.89 (m, 2H),6.15 (d, J = 16.48 Hz, 1H), 5.32 (dd, J = 6.87, 16.33 Hz, 1H), 3.75 (brd, J = 13.12 Hz, 2H), 2.83 (br s, 2H), 2.34 (br s, 1H), 2.24 (br s, 1H),1.59 (br d, J = 12.82 Hz, 2H), 1.15 (br d, J = 8.54 Hz, 4H), 1.07 (br d,J = 2.75 Hz, 2H). A2 56

MS (ESI) m/z: 507.3 [M + H]⁺; EC₅₀ = 3; ¹H NMR (500 MHz, DMSO-d₆) δ 7.82(d, J = 8.85 Hz, 2H), 7.62-7.67 (m, 2H), 7.54-7.60 (m, 1H), 7.03 (br d,J = 8.85 Hz, 2H), 6.17 (d, J = 16.48 Hz, 1H), 5.32 (dd, J = 6.87, 16.33Hz, 1H), 3.74 (br d, J = 13.12 Hz, 2H), 2.81 (br t, J = 11.44 Hz, 2H),2.28-2.41 (m, 1H), 2.23 (br s, 1H), 1.62 (br d, J = 11.90 Hz, 2H),1.12-1.24 (m, 4H), 1.03-1.11 (m, 2H). E 57

MS (ESI) m/z: 516.9 [M + H]⁺; EC₅₀ = 45; ¹H NMR (500 MHz, DMSO-d₆) δ7.63- 7.71 (m, 3H), 7.59 (br d, J = 7.32 Hz, 1H), 6.81-6.89 (m, 2H),6.15 (d, J = 16.48 Hz, 1H), 5.32 (dd, J = 6.87, 16.33 Hz, 1H), 3.75 (brd, J = 13.12 Hz, 2H), 2.83 (br s, 2H), 2.34 (br s, 1H), 2.24 (br s, 1H),1.59 (br d, J = 12.82 Hz, 2H), 1.15 (br d, J = 8.54 Hz, 4H), 1.07 (br d,J = 2.75 Hz, 2H). A2 58

MS (ESI) m/z: 602.1 [M + H]⁺; EC₅₀ = 24; ¹H NMR (500 MHz, DMSO-d₆) δ8.21 (s, 1H), 8.08 (d, J = 9.51 Hz, 1H), 7.86 (br dd, J = 1.98, 9.55 Hz,1H), 7.81 (d, J = 8.25 Hz, 2H), 7.68-7.76 (m, 1H), 7.01-7.08 (m, 1H),6.12-6.21 (m, 1H), 6.06 (d, J = 6.98 Hz, 1H), 3.97 (br d, J = 12.71 Hz,2H), 3.02 (br t, J = 11.70 Hz, 2H), 2.40-2.48 (m, 1H), 2.08 (s, 1H),1.76 (br d, J = 11.44 Hz, 2H), 1.38 (br d, J = 10.10 Hz, 2H), 1.03 (brdd, J = 2.27, 8.08 Hz, 2H), 0.91- 0.96 (m, 2H). A2 59

MS (ESI) m/z: 523.2 [M + H]⁺; EC₅₀ = 214; ¹H NMR (500 MHz, DMSO-d₆) δ7.65 (s, 2H), 7.56- 7.62 (m, 1H), 7.10-7.15 (m, 2H), 6.83-6.90 (m, 2H),6.17 (d, J = 16.17 Hz, 1H), 5.34 (dd, J = 7.02, 16.17 Hz, 1H), 3.53 (brs, 1H), 2.89 (s, 1H), 2.73 (s, 2H), 2.31-2.38 (m, 1H), 2.11-2.20 (m,1H), 1.60-1.67 (m, 2H), 1.38 (br d, J = 2.44 Hz, 2H), 1.25 (br d, J =11.90 Hz, 2H), 1.14-1.19 (m, 2H), 1.05- 1.11 (m, 2H), 1.04 (br d, J =2.75 Hz, 2H). A2 60

MS (ESI) m/z: 523.2 [M + H]⁺; EC₅₀ = 17; ¹H NMR (500 MHz, DMSO-d₆) δ7.65 (s, 2H), 7.56-7.62 (m, 1H), 7.10-7.15 (m, 2H), 6.83-6.90 (m, 2H),6.17 (d, J = 16.17 Hz, 1H), 5.34 (dd, J = 7.02, 16.17 Hz, 1H), 3.53 (brs, 1H), 2.89 (s, 1H), 2.73 (s, 2H), 2.31-2.38 (m, 1H), 2.11-2.20 (m,1H), 1.60-1.67 (m, 2H), 1.38 (br d, J = 2.44 Hz, 2H), 1.25 (br d, J =11.90 Hz, 2H), 1.14-1.19 (m, 2H), 1.05-1.11 (m, 2H), 1.04 (br d, J =2.75 Hz, 2H). A2 61

MS (ESI) m/z: 505.2 [M + H]⁺; EC₅₀ = 41; ¹H NMR (500 MHz, DMSO-d₆) δ7.79 (br d, J = 8.54 Hz, 2H), 7.63-7.68 (m, 2H), 7.60 (br d, J = 7.02Hz, 1H), 6.64 (br d, J = 8.54 Hz, 2H), 6.09-6.17 (m, 1H), 5.13 (dd, J =9.00, 16.02 Hz, 1H), 2.34 (br t, J = 5.04 Hz, 1H), 1.68 (br s, 2H), 1.37(br d, J = 8.85 Hz, 1H), 1.13-1.18 (m, 2H), 1.07 (br d, J = 2.44 Hz, 2H)additional signals were lost due to water suppression. A1 62

MS (ESI) m/z: 523.2 [M + H]⁺; EC₅₀ = 20; ¹H NMR (500 MHz, DMSO-d₆) δ7.85 (br d, J = 8.84 Hz, 2H), 7.70 (br s, 1H), 7.52-7.59 (m, 3H), 7.08(br d, J = 8.85 Hz, 2H), 6.11 (d, J = 16.17 Hz, 1H), 5.62 (dd, J = 6.87,16.33 Hz, 1H), 3.84 (br d, J = 12.82 Hz, 2H), 2.85 (br t, J = 11.60 Hz,2H), 2.31 (br dd, J = 5.04, 8.39 Hz, 2H), 1.69 (br d, J = 11.90 Hz, 2H),1.30 (br d, J = 9.46 Hz, 2H), 1.12-1.20 (m, 2H), 1.04-1.09 (m, 2H). A163

MS (ESI) m/z: 507.2 [M + H]⁺; EC₅₀ = 216; ¹H NMR (500 MHz, DMSO-d₆) δ7.67 (br d, J = 7.93 Hz, 2H), 7.60 (br s, 1H), 7.54 (br s, 1H), 7.39 (brd,J = 7.32 Hz, 1H), 7.20-7.29 (m, 1H), 6.86-6.93 (m, 1H), 6.19 (br d, J= 16.17 Hz, 1H), 5.35 (br dd, J = 6.41, 16.48 Hz, 1H), 3.58-3.65 (m,1H), 2.74 (br s, 2H), 2.37 (br s, 1H), 2.18 (br s, 1H), 1.92 (s, 2H),1.65 (br d, J = 12.82 Hz, 2H), 1.27 (br d, J = 10.68 Hz, 2H), 1.17 (brd, J = 5.80 Hz, 2H), 1.09 (br s, 2H). A1 64

MS (ESI) m/z: 508.2 [M + H]⁺; EC₅₀ = 30; ¹H NMR (500 MHz, DMSO-d₆) δ7.65 (br d, J = 7.63 Hz, 2H), 7.58 (br d, J = 7.32 Hz, 1H), 6.91-7.04(m, 1H), 6.10-6.21 (m, 1H), 5.28-5.39 (m, 1H), 4.27 (br d, J = 8.24 Hz,2H), 2.91 (br s, 2H), 2.34 (br s, 2H), 1.54-1.67 (m, 2H), 1.15 (br d, J= 6.71 Hz, 4H), 1.07 (br s, 2H) additional signals were lost due towater suppression. E 65

MS (ESI) m/z: 556.1 [M + H]⁺; EC₅₀ = 189; ¹H NMR (500 MHz, DMSO-d₆) δ8.14-8.21 (m, 1H), 8.07 (br d, J = 8.55 Hz, 1H), 7.91 (br d, J = 9.16Hz, 1H), 7.64-7.69 (m, 2H), 7.61 (br d, J = 7.32 Hz, 1H), 7.30 (br d, J= 9.46 Hz, 1H), 6.80 (br s, 1H), 6.09-6.21 (m, 1H), 5.16 (br dd, J =9.00, 16.02 Hz, 1H), 3.70 (br d, J = 9.77 Hz, 2H), 2.35 (br s, 1H), 1.72(br s, 2H), 1.39-1.46 (m, 1H), 1.13-1.19 (m, 2H), 1.08 (br d, J = 2.75Hz, 2H) additional signals were lost due to water suppresiion. E 66

MS (ESI) m/z 533.1 [M + H]⁺; EC₅₀ = 227. A2 67

MS (ESI) m/z: 551.2 [M + H]⁺; EC₅₀ = 1212; ¹H NMR (500 MHz, DMSO-d₆) δ8.47 (br s, 1H), 7.95 (br d, J = 9.16 Hz, 1H), 7.71-7.79 (m, 1H), 7.63(br s, 1H), 7.45-7.55 (m, 4H), 6.07 (br d, J = 16.17 Hz, 1H), 5.53-5.63(m, 1H), 4.02 (br d, J = 12.82 Hz, 2H), 2.98 (br s, 2H), 2.21-2.35 (m,2H), 1.69 (br d, J = 11.90 Hz, 2H), 1.29 (br d, J = 10.07 Hz, 2H),1.05-1.14 (m, 2H), 0.96-1.04 (m, 2H). A2 68

MS (ESI) m/z: 534.1 [M + H]⁺; EC₅₀ = 17; ¹H NMR (500 MHz, DMSO-d₆) δ7.61- 7.69 (m, 3H), 7.49-7.61 (m, 2H), 6.54 (br s, 1H), 6.46 (br s, 1H),6.12 (br d, J = 16.17 Hz, 1H), 5.01-5.14 (m, 1H), 3.63 (br d, J = 4.58Hz, 1H), 3.11-3.18 (m, 2H), 2.32 (br d, J = 3.36 Hz, 1H), 1.60 (br s,2H), 1.41 (br d, J = 7.02 Hz, 1H), 1.15 (br d, J = 5.80 Hz, 2H), 1.05(br d, J = 2.75 Hz, 2H) additional signals were lost due to watersuppression. A2 69

MS (ESI) m/z: 534.4 [M + H]⁺; EC₅₀ = 31; ¹H NMR (500 MHz, DMSO-d₆) δ8.67 (br s, 1H), 7.92 (br s, 1H), 7.64-7.70 (m, 2H), 7.60 (br d, J =7.32 Hz, 1H), 7.49 (br d, J = 9.16 Hz, 1H), 7.21 (br s, 1H), 6.20 (d, J= 16.17 Hz, 1H), 5.36 (dd, J = 6.71, 16.17 Hz, 1H), 3.93 (br d, J =12.82 Hz, 2H), 2.95 (br s, 2H), 2.35- 2.40 (m, 1H), 2.26-2.34 (m, 1H),1.69 (br d, J = 11.60 Hz, 2H), 1.20-1.33 (m, 3H), 1.14-1.19 (m, 2H),1.09 (br d, J = 2.75 Hz, 2H). A2 70

MS (ESI) m/z: 480.1 [M + H]⁺; EC₅₀ = 377; ¹H NMR (500 MHz, DMSO-d₆) δ7.70 (d, J = 8.6 Hz, 2H), 7.67-7.62 (m, 2H), 7.59 (dd, J = 9.2, 6.8 Hz,1H), 6.50 (d, J = 8.6 Hz, 2H), 6.12 (d, J = 16.1 Hz, 1H), 5.18 (dd, J =16.1, 8.7 Hz, 1H), 3.56 (d, J = 9.9 Hz, 2H), 3.20-3.18 (two protonsignals were lost due to water suppression), 2.32 (td, J = 8.5, 4.3 Hz,1H), 1.71-1.62 (m, 2H), 1.36 (dt, J = 8.8, 3.3 Hz, 1H), 1.23-1.01 (m,4H). F 71

MS (ESI) m/z: 558.1 [M + H]⁺; EC₅₀ = 83; ¹H NMR (500 MHz, DMSO-d₆) δ7.77 (d, J = 8.6 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H), 7.60 (dd, J = 9.1,7.0 Hz, 1H), 6.54 (d, J = 8.7 Hz, 2H), 6.13 (d, J = 16.1 Hz, 1H), 5.14(dd, J = 16.1, 8.9 Hz, 1H), 3.58 (d, J = 10.2 Hz, 2H), 3.31 (s, 3H),3.20-3.18 (two protons signals were lost due to water suppression),2.44-2.25 (m, 1H), 1.69 (s, 2H), 1.37-1.24 (m, 1H), 1.24-0.99 (m, 4H). G72

MS (ESI) m/z: 600.9 [M + H]⁺; EC₅₀ = 98; ¹H NMR (500 MHz, Methanol-d₄) δ8.71 (s, 2H), 8.25 (s, 1H), 8.07 (d, J = 9.35 Hz, 1H), 7.36-7.52 (m,1H), 6.79 (br s, 1H), 6.16 (d, J = 16.23 Hz, 1H), 5.27 (dd, J = 8.80,15.96 Hz, 1H), 3.72 (s, 2H), 3.45-3.54 (m, 2H), 2.23-2.30 (m, 1H),1.83-1.89 (m, 2H), 1.39- 1.43 (m, 1H), 1.17-1.21 (m, 2H), 1.14-1.17 (m,2H). A2 73

MS (ESI) m/z: 533.0 [M + H]⁺; EC₅₀ = 673; ¹H NMR (500 MHz, Methanol-d₄)δ 9.21 (s, 1H), 8.72 (s, 2H), 8.70 (s, 1H), 8.12 (s, 1H), 7.62 (br d, J= 7.43 Hz, 1H), 7.25 (br s, 1H), 6.16 (d, J = 16.23 Hz, 1H), 5.24-5.35(m, 1H), 3.80 (d, J = 10.18 Hz, 2H), 3.57 (br d, J = 9.35 Hz, 2H), 2.27(s, 1H), 1.18- 1.22 (m, 2H), 1.13-1.18 (m, 2H). A2 74

MS (ESI) m/z: 534.4 [M + H]⁺; EC₅₀ = 308; ¹H NMR (500 MHz, DMSO-d₆) δ8.16 (s, 1H), 8.05 (d, J = 9.46 Hz, 1H), 7.76 (br d, J = 6.41 Hz, 1H),7.43-7.54 (m, 3H), 6.68 (br s, 1H), 6.11 (d, J = 15.87 Hz, 1H), 5.31(dd, J = 9.00, 16.02 Hz, 1H), 3.85 (br s, 1H), 3.70 (br d, J = 10.07 Hz,1H), 2.98 (s, 1H), 2.92 (br d, J = 6.10 Hz, 1H), 2.32 (br d, J = 4.88Hz, 1H), 1.47-1.56 (m, 1H), 1.39-1.45 (m, 1H), 1.36 (br d, J = 6.41 Hz,1H), 1.12-1.18 (m, 2H), 1.02-1.10 (m, 2H). A2 75

MS (ESI) m/z: 600.1 [M + H]⁺; EC₅₀ = 577; ¹H NMR (500 MHz, DMSO-d₆) δ8.13 (s, 1H), 8.01 (br d, J = 9.34 Hz, 1H), 7.87 (br d, J = 7.74 Hz,1H), 7.68-7.80 (m, 2H), 7.46 (br d, J = 7.41 Hz, 1H), 7.41 (dd, J =1.85, 9.42 Hz, 1H), 6.66 (br s, 1H), 6.02 (d, J = 16.16 Hz, 1H),5.13-5.24 (m, 1H), 3.65 (br d, J = 10.10 Hz, 2H), 3.45 (br d, J = 9.26Hz, 2H), 2.24 (br s, 1H), 1.72 (br s, 2H), 1.33 (br d, J = 8.67 Hz, 1H),1.11 (br dd, J = 2.57, 8.12 Hz, 2H), 0.99-1.04 (m, 2H). A2 76

MS (ESI) m/z: 532.2 [M + H]⁺; EC₅₀ = 413; ¹H NMR (500 MHz, Methanol-d₄)δ 9.19 (s, 1H), 8.67 (s, 1H), 8.10 (d, J = 9.08 Hz, 1H), 7.88 (d, J =7.43 Hz, 1H), 7.69-7.81 (m, 2H), 7.59 (dd, J = 1.65, 9.08 Hz, 1H), 7.45(d, J = 7.15 Hz, 1H), 7.21 (s, 1H), 6.10 (d, J = 16.23 Hz, 1H), 5.21(dd, J = 8.67, 16.09 Hz, 1H), 3.77 (d, J = 9.90 Hz, 2H), 3.55 (br s,2H), 2.22 (s, 1H), 1.76 (br s, 2H), 1.35-1.39 (m, 1H), 1.12-1.19 (m,4H). A2 77

MS (ESI) m/z: 557.1 [M + H]⁺; EC₅₀ = 786; ¹H NMR (500 MHz, DMSO-d₆) δ8.80 (s, 2H), 8.16 (s, 1H), 7.57 (br d, J = 11.61 Hz, 1H), 6.12 (d, J =15.99 Hz, 1H), 5.30 (dd, J = 8.54, 16.11 Hz, 1H), 3.66-3.74 (m, 2H),3.41-3.59 (m, 2H), 2.27-2.36 (m, 1H), 1.80 (br s, 2H), 1.38-1.46 (m,1H), 1.17 (br dd, J = 2.57, 8.20 Hz, 2H), 1.03-1.12 (m, 2H). A2 78

MS (ESI) m/z: 538.8 [M + H]⁺; EC₅₀ = 515; ¹H NMR (500 MHz, DMSO-d₆) δ8.76 (s, 2H), 8.26 (s, 1H), 7.80 (br d, J = 8.41 Hz, 1H), 7.41 (d, J =8.41 Hz, 1H), 6.09 (d, J = 16.07 Hz, 1H), 5.25 (dd, J = 8.58, 16.07 Hz,1H), 3.58-3.70 (m, 4H), 2.28 (br t, J = 4.88 Hz, 1H), 1.75 (br s, 2H),1.36 (br d, J = 8.50 Hz, 1H), 1.13 (br dd, J = 2.61, 8.16 Hz, 2H),1.00-1.06 (m, 2H). A1 79

MS (ESI) m/z: 533.0 [M + H]⁺; EC₅₀ = 1160; ¹H NMR (500 MHz, DMSO-d₆) δ8.85 (s, 2H), 8.47 (s, 1H), 8.37 (br d, J = 9.46 Hz, 1H), 8.15 (s, 1H),7.85 (br d, J = 8.54 Hz, 1H), 7.15 (br d, J = 6.41 Hz, 1H), 6.09 (d, J =16.17 Hz, 1H), 5.33 (dd, J = 8.85, 16.17 Hz, 1H), 3.98 (br d, J = 11.60Hz, 2H), 3.77 (br s, 1H), 1.60-3.61 (m, 4H), 1.41-1.51 (m, 1H),1.13-1.22 (m, 2H), 1.05-1.13 (m, 2H). A2 80

MS (ESI) m/z: 563.2 [M + H]⁺; EC₅₀ = 38; ¹H NMR (500 MHz, DMSO-d₆) δ8.83 (s, 2H), 7.92 (br d, J = 9.17 Hz, 1H), 7.43 (s, 1H), 7.30 (br d, J= 9.17 Hz, 1H), 6.86 (s, 1H), 6.13 (d, J = 16.07 Hz, 1H), 5.31 (dd, J =8.71, 16.03 Hz, 1H), 4.08 (s, 3H), 3.67 (br d, J = 9.76 Hz, 2H), 3.40(br d, J = 8.92 Hz, 1H), 2.35 (br s, 1H), 1.91 (s, 1H), 1.80 (br s, 2H),1.41-1.47 (m, 1H), 1.18 (br dd, J = 2.52, 8.16 Hz, 2H), 1.06-1.13 (m,2H). A2 81

MS (ESI) m/z: 539.0 [M + H]⁺; EC₅₀ = 89. A1 82

MS (ESI) m/z: 532.9 [M + H]⁺; EC₅₀ = 267; ¹H NMR (500 MHz, Methanol-d₄)δ 7.19 (s, 2H), 6.94 (br d, J = 8.53 Hz, 1H), 6.60 (dd, J = 4.26, 8.94Hz, 2 H), 5.99 (br d, J = 9.63 Hz, 1H), 5.38 (s, 1H), 4.62 (d, J = 15.96Hz, 1H), 3.75 (dd, J = 8.80, 15.96 Hz, 1H), 2.24 (d, J = 10.18 Hz, 2H),1.98 (br d, J = 9.35 Hz, 2H), 0.73 (s, 1H), 0.27 (br s, 2H), −0.11 (brd, J = 8.80 Hz, 1H), −0.39- −0.32 (m, 4H). A2 83

MS (ESI) m/z: 603.0 [M + H]⁺; EC₅₀ = 42; ¹H NMR (400 MHz, Methanol-d₄) δ7.16 (s, 2H), 6.76 (s, 1H), 6.57 (d, J = 9.46 Hz, 1H), 6.21 (dd, J =2.64, 9.68 Hz, 1H), 5.63 (br s, 1H), 4.65 (dd, J = 1.10, 16.29 Hz, 1H),3.91-4.02 (m, 1H), 2.35-2.47 (m, 2H), 1.42-1.54 (m, 2H), 0.66-0.86 (m,2H), 0.24 (br s, 2H), −0.21- −0.06 (m, 2H), −0.41- −0.32 (m, 4H). A2 84

MS (ESI) m/z: 569.0 [M + H]⁺; EC₅₀ = 215; ¹H NMR (400 MHz, Methanol-d₄)δ 7.19 (s, 1H), 7.06 (d, J = 4.84 Hz, 1H), 6.75 (s, 1H), 6.57 (d, J =9.68 Hz, 1H), 6.21 (dd, J = 2.64, 9.68 Hz, 1H), 5.97 (d,J = 4.84 Hz,1H), 5.65 (br s, 1H), 4.64 (dd, J = 1.10, 16.29 Hz, 1H), 4.05 (dd, J =7.04, 16.29 Hz, 1H), 2.43 (br d, J = 13.20 Hz, 2H), 1.49 (br d, J = 1.32Hz, 2H), 0.75-0.86 (m, 1H), 0.68 (s, 1H), 0.21-0.34 (m, 2H), −0.13 (brs, 2H), −0.46- −0.34 (m, 4H). A2 85

MS (ESI) m/z: 542.0 [M + H]⁺; EC₅₀ = 156; ¹H NMR (500 MHz, Methanol-d₄)δ 8.73 (s, 2H), 8.11 (d, J = 8.3 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 6.23(d, J = 16.2 Hz, 1H), 5.51 (dd, J = 16.2, 7.2 Hz, 1H), 4.19 (br d, J =11.3 Hz, 2H), 3.31-3.26 (m, 2H), 2.44 (br dd, J = 6.9, 3.6 Hz, 1H),2.34-2.22 (m, 1H), 1.82 (br d, J = 12.4 Hz, 2H), 1.50-1.32 (m, 2H),1.26-1.15 (m, 4H). A1 86

MS (ESI) m/z: 487.9 [M + H]⁺; EC₅₀ = 1013; ¹H NMR (500 MHz, DMSO-d₆) δ7.71 (s, 1H), 7.65- 7.52 (m, 3H), 6.11 (d, J = 16.1 Hz, 1H), 5.16 (dd, J= 16.0, 8.6 Hz, 1H), 3.69-3.53 (m, 2H), 2.55 (m, 2H), 2.34-2.24 (m, 1H),1.69 (br s, 2H), 1.37-1.29 (m, 1H), 1.21-1.12 (m, 2H), 1.09-1.01 (m,2H). A2 87

MS (ESI) m/z: 541.0 [M + H]⁺; EC₅₀ = 26; ¹H NMR (500 MHz, DMSO-d₆) δ7.97 (d, J = 8.4 Hz, 1H), 7.90 (br d, J = 7.7 Hz, 1H), 7.82-7.69 (m,3H), 7.47 (br d, J = 7.5 Hz, 1H), 6.07 (d, J = 16.2 Hz, 1H), 5.39 (dd, J= 16.2, 6.8 Hz, 1H), 4.01 (br d, J = 13.3 Hz, 2H), 3.24 (br t, J = 11.6Hz, 2H), 2.39-2.21 (m, 2H), 1.69 (br d, J = 10.9 Hz, 2H), 1.28-1.11 (m,4H), 1.08-1.00 (m, 2H). A1 88

MS (ESI) m/z: 565.0 [M + H]⁺; EC₅₀ = 5; ¹H NMR (500 MHz, Methanol-d₄) δ8.71 (s, 2H), 8.15 (d, J = 9.63 Hz, 1H), 7.89 (dd, J = 2.48, 9.63 Hz,1H), 7.76 (s, 1H), 7.44 (d, J = 2.48 Hz, 1H), 6.20 (dd, J = 1.10, 16.23Hz, 1H), 5.43-5.54 (m, 1H), 4.35 (s, 3H), 3.98 (br d, J = 13.20 Hz, 2H),2.97-3.07 (m, 2H), 2.32-2.40 (m, 1H), 2.22-2.31 (m, 1H), 1.80 (br d, J =11.00 Hz, 2H), 1.40 (br dd, J = 2.34, 11.42 Hz, 2H), 1.19-1.22 (m, 2H),1.17 (td, J = 2.79, 5.16 Hz, 2H). A2 89

MS (ESI) m/z: 534.9 [M + H]⁺; EC₅₀ = 31; ¹H NMR (500 MHz, Methanol-d₄) δ8.72 (s, 2H), 7.83 (d, J = 8.80 Hz, 1H), 7.69 (br s, 1H), 6.66 (br s,1H), 6.50 (br s, 1H), 6.13 (d, J = 15.96 Hz, 1H), 5.19- 5.31 (m, 1H),3.75 (s, 3H), 3.68 (br d, J = 82.5 Hz, 2H), 3.27 (ddd, J = 1.10, 2.20,7.15 Hz, 2H), 2.22-2.31 (m, 1H), 1.69 (br s, 2H), 1.48-1.55 (m, 1H),1.18-1.22 (m, 2H), 1.16 (br s, 2H). A2 90

MS (ESI) m/z: 534.1 [M + H]⁺; EC₅₀ = 74; ¹H NMR (500 MHz, DMSO-d₆) δ9.12 (s, 1H), 8.44 (s, 1H), 7.98 (d, J = 9.4 Hz, 1H), 7.93 (d, J = 7.7Hz, 1H), 7.84-7.80 (m, 1H), 7.79-7.74 (m, 1H), 7.73-7.68 (m, 1H), 7.53(d, J = 7.2 Hz, 1H), 7.41 (s, 1H), 6.11 (d, J = 16.2 Hz, 1H), 5.40 (dd,J = 16.4, 7.0 Hz, 1H), 3.91 (br d, J = 12.7 Hz, 2H), 2.90 (br t, J =11.4 Hz, 2H), 2.35-2.30 (m, 1H), 2.29-2.22 (m, 1H), 1.67 (br d, J = 11.6Hz, 2H), 1.32-1.22 (m, 2H), 1.18-1.13 (m, 2H), 1.10-1.05 (m, 2H). A2 91

MS (ESI) m/z: 599.0 [M + H]⁺; EC₅₀ = 4; ¹H NMR (400 MHz, Methanol-d₄) δ8.73 (s, 2H), 8.10 (d, J = 9.46 Hz, 1H), 7.80 (s, 1H), 7.45-7.53 (m,1H), 6.91 (d, J = 2.42 Hz, 1H), 6.12-6.23 (m, 1H), 5.29 (dd, J = 8.80,16.07 Hz, 1H), 3.77 (d, J = 10.12 Hz, 2H), 3.54 (br s, 2H), 2.28 (s,1H), 1.82 (br s, 2H), 1.40-1.47 (m, 1H), 1.12-1.25 (m, 5H). A2 92

MS (ESI) m/z: 601.0 [M + H]⁺; EC₅₀ = 3; ¹H NMR (400 MHz, Methanol-d₄) δ8.71 (s, 2H), 8.10 (br d, J = 2.64 Hz, 1H), 7.74-7.87 (m, 2H), 7.42 (s,1H), 7.31 (d, J = 2.42 Hz, 1H), 6.20 (dd, J = 1.10, 16.07 Hz, 1H),5.44-5.57 (m, 1H), 3.96 (br d, J = 12.98 Hz, 2H), 3.01 (br t, J = 11.33Hz, 2H), 2.23-2.38 (m, 2H), 1.81 (br d, J = 11.00 Hz, 2H), 1.41-1.51 (m,2H), 1.29 (s, 1H), 1.14-1.23 (m, 4H). A2 93

MS (ESI) m/z: 539.0 [M + H]⁺; EC₅₀ = 280; ¹H NMR (500 MHz, DMOS-d₆) δ8.86 (br s, 2H), 7.68 (br s, 2H), 7.41 (br s, 1H), 6.17 (br d, J = 15.1Hz, 1H), 5.32 (br s, 1H), 3.81-3.61 (m, 4H), 2.38 (br s, 1H), 1.83 (brs, 2H), 1.45 (br s, 1H), 1.25-1.06 (m, 4H). A1 94

MS (ESI) m/z: 536.1 [M + H]⁺; EC₅₀ = 409; ¹H NMR (400 MHz, CDCl₃) δ7.48-7.75 (m, 3H), 7.34-7.43 (m, 2H), 7.17 (s, 1H), 6.60 (s, 1H),6.03-6.15 (m, 1H), 5.69 (dd, J = 7.04, 16.07 Hz, 1H), 4.18-4.27 (m, 1H),3.63 (br d, J = 12.32 Hz, 2H), 2.80 (br d, J = 1.98 Hz, 2H), 2.51 (s,3H), 2.20 (tdd, J = 3.71, 7.37, 10.95 Hz, 1H), 2.11 (tt, J = 5.12, 8.42Hz, 1H), 1.60 (br d, J = 2.42 Hz, 2H), 1.39-1.48 (m, 2H), 1.21-1.24 (m,2H), 1.10-1.18 (m, 2H). A2 95

MS (ESI) m/z: 539.0 [M + H]⁺; EC₅₀ = 108; ¹H NMR (500 MHz, DMSO-d₆) δ8.87 (s, 2H), 8.33 (br d, J = 9.1 Hz, 1H), 7.14 (s, 1H), 6.91 (dd, J =9.1, 1.7 Hz, 1H), 6.16 (d, J = 16.2 Hz, 1H), 5.29 (dd, J = 16.1, 8.9 Hz,1H), 3.64 (d, J = 9.9 Hz, 2H), 3.37 (br d, J = 9.1 Hz, 2H), 2.42-2.34(m, 1H), 1.81 (br s, 2H), 1.46-1.39 (m, 1H), 1.22-1.15 (m, 2H),1.14-1.08 (m, 2H). A2 96

MS (ESI) m/z: 482.0 [M + H]⁺; EC₅₀ = 66; ¹H NMR (400 MHz, Methanol-d₄) δ8.72 (s, 2H), 7.82 (d, J = 8.80 Hz, 2H), 6.55 (d, J = 9.02 Hz, 2H), 6.14(d, J = 16.07 Hz, 1H), 5.19-5.31 (m, 1H), 3.63 (d, J = 9.90 Hz, 2H),3.37 (br d, J = 1.10 Hz, 2H), 2.22- 2.31 (m, 1H), 1.68-1.75 (m, 2H),1.37 (br d, J = 8.80 Hz, 1H), 1.12-1.23 (m, 4H). A1 97

MS (ESI) m/z: 603.1 [M + H]⁺; EC₅₀ = 21; ¹H NMR (400 MHz, DMSO-d₆) δ8.85 (dd, J = 4.6, 1.6 Hz, 1H), 8.13 (s, 1H), 8.05-7.97 (m, 2H),7.84-7.74 (m, 2H), 6.97 (s, 1H), 6.06 (dd, J = 16.3, 1.3 Hz, 1H), 5.36(dd, J = 16.3, 6.9 Hz, 1H), 3.87 (d, J = 13.1 Hz, 2H), 2.93 (t, J = 12.3Hz, 2H), 2.34-2.07 (m, 2H), 1.69-1.59 (m, 2H), 1.30-1.14 (m, 2H), 1.14-0.89 (m, 4H). A2 98

MS (ESI) m/z: 601.1 [M + H]⁺; EC₅₀ = 3; ¹H NMR (400 MHz, DMSO-d₆) δ 8.85(dd, J = 4.8, 1.5 Hz, 1H), 8.03 (dd, J = 8.0, 1.6 Hz, 1H), 7.89 (d, J =9.4 Hz, 1H), 7.85-7.78 (m, 1H), 7.68 (dd, J = 9.5, 2.8 Hz, 1H), 7.65 (t,J = 72.6 Hz, 1H), 7.62 (s, 1H), 7.06 (d, J = 2.7 Hz, 1H), 6.07 (dd, J =16.3, 1.3 Hz, 1H), 5.37 (dd, J = 16.3, 7.0 Hz, 1H), 3.83 (d, J = 12.7Hz, 2H), 2.83 (t, J = 12.1 Hz, 2H), 2.33-2.13 (m, 2H), 1.63 (d, J = 12.8Hz, 2H), 1.32-1.14 (m, 2H), 1.14-0.82 (m, 4H). A2 99

MS (ESI) m/z: 600.2 [M + H]⁺; EC₅₀ = 3; ¹H NMR (500 MHz, DMSO-d₆) δ8.05-7.66 (m, 7H), 7.63- 7.48 (m, 1H), 7.12 (br s, 1H), 6.11 (br d, J =15.1 Hz, 1H), 5.41 (br d, J = 11.0 Hz, 1H), 3.86 (br s, 2H), 2.91 (br s,2H), 2.36-2.25 (m, 2H), 1.69 (br d, J = 6.1 Hz, 2H), 1.27 (br d, J = 8.3Hz, 2H), 1.19-1.05 (m, 4H). A2 100

MS (ESI) m/z: 564.2 [M + H]⁺; EC₅₀ = 4; ¹H NMR (500 MHz, DMSO-d₆) δ7.98- 7.91 (m, 2H), 7.85-7.80 (m, 1H), 7.80- 7.75 (m, 1H), 7.69 (dd, J =9.5, 2.6 Hz, 1H), 7.53 (d, J = 7.4 Hz, 1H), 7.49 (s, 1H), 7.23 (d, J =2.8 Hz, 1H), 6.11 (d, J = 15.7 Hz, 1H), 5.40 (dd, J = 16.4, 7.0 Hz, 1H),4.12 (s, 3H), 3.83 (br d, J = 12.9 Hz, 2H), 2.85 (br t, J = 11.4 Hz,2H), 2.36-2.30 (m, 1H), 2.27-2.19 (m, 1H), 1.68 (br d, J = 11.3 Hz, 2H),1.32-1.23 (m, 2H), 1.18-1.13 (m, 2H), 1.10-1.04 (m, 2H). A2 101

MS (ESI) m/z: 535.0 [M + H]⁺; EC₅₀ = 47; ¹H NMR (500 MHz, Methanol-d₄) δ9.19 (br s, 1H), 8.73 (s, 2H), 8.63 (br s, 1H), 8.08 (br d, J = 9.1 Hz,1H),7 .89 (br d, J = 8.3 Hz, 1H), 7.54 (br s, 1H), 6.23 (d, J = 16.2 Hz,1H), 5.51 (dd, J = 16.2, 6.9 Hz, 1H), 4.04 (br d, J = 12.7 Hz, 2H), 3.06(br t, J = 12.0 Hz, 2H), 2.39 (br d, J = 7.2 Hz, 1H), 2.33-2.25 (m, 1H),1.82 (br d, J = 12.1 Hz, 2H), 1.49-1.37 (m, 2H), 1.26-1.15 (m, 2H). A2102

MS (ESI) m/z: 483.0 [M + H]⁺; EC₅₀ = 1270; ¹H NMR (500 MHz, DMSO-d₆) δ8.82 (s, 2H), 8.55 (s, 1H), 7.87 (br d, J = 8.84 Hz, 1H), 6.45 (br d, J= 8.92 Hz, 1H), 6.11 (br d, J = 16.07 Hz, 1H), 5.24 (br dd, J = 8.50,15.99 Hz, 1H), 1.25-3.90 (8H), 1.12-1.21 (m, 2H), 1.07 (br d, J = 1.85Hz, 2H). A1 103

MS (ESI) m/z: 535.2 [M + H]⁺; EC₅₀ = 189; ¹H NMR (400 MHz, Methanol-d₄)δ 9.12 (s, 1H), 8.84-8.67 (m, 1H), 8.59 (s, 1H), 8.02 (d, J = 9.3 Hz,1H), 7.89-7.79 (m, 2H), 7.68 (dd, J = 7.9, 4.7 Hz, 1H), 7.48 (s, 1H),6.05 (dd, J = 16.3, 1.2 Hz, 1H), 5.37 (dd, J = 16.3, 7.0 Hz, 1H), 3.97(d, J = 13.0 Hz, 2H), 2.96 (t, J = 12.4 Hz, 2H), 2.33-2.20 (m, 1H), 2.14(td, J = 8.3, 4.2 Hz, 1H), 1.70 (d, J = 13.1 Hz, 2H), 1.38-1.17 (m, 2H),1.13-1.00 (m, 4H). A2 104

MS (ESI) m/z: 535.1 [M + H]⁺; EC₅₀ = 219; ¹H NMR (500 MHz, Methanol-d₄)δ 9.21 (d, J = 9.9 Hz, 1H), 8.72 (s, 2H), 7.99 (d, J = 6.6 Hz, 1H), 7.85(d, J = 6.6 Hz, 1H), 7.70 (dd, J = 9.9, 2.2 Hz, 1H), 7.25 (d, J = 2.2Hz, 1H), 6.22 (dd, J = 16.2, 0.8 Hz, 1H), 5.50 (dd, J = 16.2, 7.2 Hz,1H), 4.26 (br d, J = 13.5 Hz, 2H), 3.21 (br t, J = 11.7 Hz, 2H),2.53-2.40 (m, 1H), 2.35-2.19 (m, 1H), 1.84 (br d, J = 11.6 Hz, 2H),1.47-1.31 (m, 2H), 1.27-1.12 (m, 4H). A2 105

MS (ESI) m/z: 533.0 [M + H]⁺; EC₅₀ = 310; ¹H NMR (500 MHz, Methanol-d₄)δ 9.25 (br d, J = 9.4 Hz, 1H), 8.74 (s, 2H), 7.99 (br d, J = 6.6 Hz,1H), 7.85 (br d, J = 6.3 Hz, 1H), 7.38 (br d, J = 9.4 Hz, 1H), 6.93 (brs, 1H), 6.19 (br d, J = 16.2 Hz, 1H), 5.31 (br dd, J = 16.0, 8.5 Hz,1H), 3.86 (br d, J = 10.2 Hz, 2H), 3.68 (br d, J = 9.6 Hz, 2H), 2.30 (brd, J = 5.0 Hz, 1H), 1.87 (br s, 2H), 1.41 (br d, J = 8.0 Hz, 1H),1.28-1.13 (m, 4H). A2 106

MS (ESI) m/z: 550.2 [M + H]⁺; EC₅₀ = 330; ¹H NMR (500 MHz, DMSO-d₆) δ9.10 (s, 1H), 8.42 (s, 1H), 7.96 (br d, J = 9.16 Hz, 1H), 7.69 (br d, J= 8.54 Hz, 1H), 7.61-7.65 (m, 1H), 7.46-7.53 (m, 3H), 7.41 (br s, 1H),6.01-6.11 (m, 1H), 5.57 (br dd, J = 6.71, 16.17 Hz, 1H), 3.91 (br d, J =12.21 Hz, 2H), 2.89 (br t, J = 11.60 Hz, 2H), 2.25 (br s, 2H), 1.68 (brd, J = 12.21 Hz, 2H), 1.28 (br d, J = 10.68 Hz, 2H), 1.09 (br d, J =7.63 Hz, 2H), 0.97-1.02 (m, 2H). A2 107

MS (ESI) m/z: 539.0 [M + H]⁺; EC₅₀ = 472; ¹H NMR (500 MHz, Methanol-d₄)δ 8.74 (s, 2H), 7.90 (br d, J = 8.8 Hz, 1H), 7.07 (br s, 1H), 6.96 (brd, J = 8.8 Hz, 1H), 6.16 (d, J = 16.0 Hz, 1H), 5.28 (dd, J = 16.1, 8.7Hz, 1H), 3.74-3.64 (m, 2H), 3.40 (br d, J = 9.1 Hz, 2H), 2.36-2.23 (m,1H), 1.82-1.70 (m, 2H), 1.48-1.41 (m, 1H), 1.23-1.17 (m, 4H). A2 108

MS (ESI) m/z: 608.2 [M + H]⁺; EC₅₀ = 22; ¹H NMR (500 MHz, DMSO-d₆) δ8.03 (br d, J = 9.34 Hz, 1H), 7.60-7.73 (m, 2H), 7.46-7.52 (m, 4H), 7.25(br s, 1H), 6.07 (br d, J = 16.24 Hz, 1H), 5.60 (br dd, J = 6.69, 16.28Hz, 1H), 5.00-5.11 (m, 1H), 3.77-3.84 (m, 1H), 2.90 (br t, J = 11.53 Hz,2H), 2.19-2.32 (m, 2H), 1.72 (br d, J = 11.86 Hz, 2H), 1.43 (br d, J =5.89 Hz, 6H), 1.28-1.38 (m, 3H), 1.13 (br d, J = 5.81 Hz, 2H), 1.01 (brd, J = 2.61 Hz, 2H). A2 109

MS (ESI) m/z: 591.2 [M + H]⁺; EC₅₀ = 25; ¹H NMR (500 MHz, DMSO-d₆) δ8.77 (s, 2H), 7.93-8.07 (m, 1H), 7.41 (s, 1H), 7.28 (br s, 1H), 6.78 (brs, 1H), 6.06 (br d, J = 16.17 Hz, 1H), 5.20 (br dd, J = 8.85, 15.87 Hz,1H), 4.97 (br s, 1H), 3.32 (br s, 2H), 2.78-2.91 (m, 1H), 2.28 (br d, J= 4.58 Hz, 1H), 1.72 (br s, 2H), 1.36 (br d, J = 3.97 Hz, 6H), 1.19 (brd, J = 6.41 Hz, 2H), 1.02 (br d, J = 2.44 Hz, 2H) additional signalswere lost due to water suppression. A2 110

MS (ESI) m/z: 593.2 [M + H]⁺; EC₅₀ = 5; ¹ H NMR (400 MHz, CDCl₃) δ 8.85(dd, J = 4.9, 1.6 Hz, 1H), 8.68 (d, J = 4.9 Hz, 1H), 7.85-7.77 (m, 1H),7.78-7.68 (m, 2H), 7.61 (dd, J = 7.8, 4.7 Hz, 1H), 7.31 (d, J = 2.5 Hz,1H), 6.03 (dd, J = 16.3, 1.2 Hz, 1H), 5.48 (dd, J = 16.2, 7.0 Hz, 1H),5.23-5.08 (m, 1H), 3.92 (d, J = 12.8 Hz, 2H), 2.96 (t, J = 12.3 Hz, 2H),2.39-2.19 (m, 1H), 2.09 (tt, J = 8.3, 5.1 Hz, 1H), 1.81 (d, J = 13.0 Hz,2H), 1.59 (d, J = 6.0 Hz, 6H) 1.53-1.35 (m, 2H), 1.31-1.06 (m, 4H). A2111

MS (ESI) m/z: 547.1 [M + H]⁺; EC₅₀ = 38; ¹H NMR (400 MHz, CDCl₃) δ 8.63(s, 2H), 8.05 (d, J = 9.3 Hz, 1H), 8.00 (s, 1H), 7.22 (d, J = 9.7 Hz,1H), 6.61 (s, 1H), 6.04 (d, J = 16.0 Hz, 1H), 5.23 (dd, J = 16.0, 8.7Hz, 1H), 3.75 (d, J = 9.7 Hz, 2H), 3.50 (d, J = 9.9 Hz, 2H), 2.63 (s,3H), 2.09 (td, J = 8.4, 4.2 Hz, 1H), 1.75 (s, 2H), 1.51-1.38 (m, 1H),1.30-1.00 (m, 4H). A2 112

MS (ESI) m/z: 556.1 [M + H]⁺; EC₅₀ = 155; ¹H NMR (500 MHz, Methanol-d₄)δ 8.74 (s, 2H), 7.94 (s, 1H), 6.36-6.11 (m, 1H), 5.52 (dd, J = 16.2, 7.2Hz, 1H), 4.22 (br d, J = 12.4 Hz, 2H), 3.31-3.24 (m, 2H), 2.56 (s, 3H),2.49-2.38 (m, 1H), 2.35-2.25 (m, 1H), 1.81 (br d, J = 12.1 Hz, 2H),1.46-1.33 (m, 2H), 1.28-1.14 (m, 4H). A1 113

MS (ESI) m/z: 607.1 [M + H]⁺; EC₅₀ = 154; ¹H NMR (500 MHz, DMSO-d6) δ8.85 (s, 2H), 8.00 (d, J = 9.0 Hz, 1H), 7.48 (s, 1H), 7.39-7.30 (m, 1H),6.87 (s, 1H), 6.15 (d, J = 16.0 Hz, 1H), 5.29 (dd, J = 16.1, 8.9 Hz,1H), 4.47 (s, 2H), 3.84 (s, 2H), 3.75-3.5 (two proton signals were lostdue to water suppression), 3.58-3.46 (m, 2H), 3.38 (s, 3H), 2.43-2.28(m, 1H), 1.82 (s, 2H), 1.49-1.38 (m, 1H), 1.31-0.90 (m, 4H). A2 114

MS (ESI): m/z 569.1 [M + H]⁺; EC₅₀ = 131; ¹H NMR (500 MHz, Methanol-d₄)δ 8.75 (br s, 2H), 8.00 (s, 1H), 7.55 (s, 1H), 6.19 (br d, J = 16.0 Hz,1H), 5.29 (br dd, J = 16.0, 8.5 Hz, 1H), 4.01 (s, 3H), 3.82 (br d, J =9.6 Hz, 2H), 3.72 (br d, J = 9.9 Hz, 2H), 2.37-2.23 (m, 1H), 1.80 (br s,2H), 1.48-1.36 (m, 1H), 1.27-1.12 (m, 4H). A1 115

MS (ESI) m/z: 535.2 [M + H]⁺; EC₅₀ = 112; ¹H NMR (400 MHz, Methanol-d₄)δ 9.27 (s, 1H), 8.88-8.94 (m, 1H), 8.74 (s, 1H), 8.31-8.37 (m, 1H), 8.16(d, J = 9.24 Hz, 1H), 7.98 (br d, J = 8.14 Hz, 1H), 7.76 (dd, J = 4.84,7.48 Hz, 1H), 7.62 (br s, 1H), 6.20 (dd, J = 1.10, 16.29 Hz, 1H), 5.44(dd, J = 7.15, 16.18 Hz, 1H), 4.10 (br d, J = 13.20 Hz, 2H), 3.09 (br s,2H), 2.31-2.42 (m, 1H), 2.25 (s, 1H), 1.80 (br d, J = 11.44 Hz, 2H),1.38 (br d, J = 9.46 Hz, 2H), 1.11-1.23 (m, 4H). A2 116

MS (ESI): m/z 550.1 [M + H]⁺; EC₅₀ = 862; ¹H NMR (500 MHz, DMSO-d₆) δ8.86 (s, 2H), 8.13 (s, 4H), 6.16 (d, J = 16.0 Hz, 1H), 5.29 (dd, J =16.0, 8.8 Hz, 1H), 3.64 (d, J = 10.2 Hz, 2H), 3.48 (d, J = 9.7 Hz, 2H),2.43-2.33 (m, 1H), 1.74 (s, 2H), 1.45-1.38 (m, 1H), 1.28-0.95 (m, 4H). H117

MS (ESI): m/z 550.1 [M + H]⁺; EC₅₀ = 494; ¹H NMR (400 MHz, DMSO-d₆) δ8.86 (s, 2H), 8.50 (s, 1H), 8.24 (d, J = 7.7 Hz, 1H), 8.20 (d, J = 7.9Hz, 1H), 7.74 (t, J = 7.8 Hz, 1H), 6.16 (d, J = 16.1 Hz, 1H), 5.29 (dd,J = 16.1, 8.8 Hz, 1H), 3.64 (d, J = 10.2 Hz, 2H), 3.48 (d, J = 11.3 Hz,2H), 2.44- 2.33 (m, 1H), 1.74 (s, 2H), 1.50-1.27 (m, 1H), 1.15 (m, 4H).H 118

MS (ESI) m/z: 539.1 [M + H]⁺; EC₅₀ = 276; ¹H NMR (500 MHz, DMSO-d₆) δ8.19 (s, 1H), 8.11 (br s, 1H), 7.89 (br d, J = 9.76 Hz, 1H), 7.67 (br d,J = 3.53 Hz, 1H), 7.47-7.58 (m, 4H), 6.01-6.17 (m, 1H), 5.63 (br dd, J =6.56, 16.24 Hz, 1H), 3.54 (br d, J = 12.45 Hz, 2H), 2.66-2.75 (m, 2H),2.27 (br d, J = 4.46 Hz, 1H), 2.14-2.22 (m, 1H), 1.71 (br d, J = 12.37Hz, 2H), 1.36 (br d, J = 11.36 Hz, 2H), 1.14 (br d, J = 8.16 Hz, 2H),1.04 (br s, 2H). A2 119

MS (ESI) m/z: 564.2 [M + H]⁺; EC₅₀ = 96; ¹H NMR (400 MHz, Methanol-d₄) δ8.59 (s, 1H), 8.12 (d, J = 9.24 Hz, 1H), 7.96 (br d, J = 2.42 Hz, 1H),7.57-7.66 (m, 1H), 7.44-7.54 (m, 4H), 6.09-6.23 (m, 1H), 5.68 (dd, J =7.04, 16.07 Hz, 1H), 4.14 (br d, J = 12.98 Hz, 2H), 3.07-3.17 (m, 5H),2.34-2.46 (m, 1H), 2.17-2.29 (m, 1H), 1.79-1.93 (m, 2H), 1.45 (br dd, J= 2.97, 12.21 Hz, 2H), 1.08-1.20 (m, 4H). A2 120

MS (ESI): m/z 619.1 [M + H]⁺; EC₅₀ = 18; ¹H NMR (400 MHz, DMSO-d₆) δ8.87 (s, 2H), 8.02 (d, J = 9.2 Hz, 1H), 7.45 (s, 1H), 7.39 (dd, J = 9.4,2.6 Hz, 1H), 6.87 (d, J = 2.6 Hz, 1H), 6.14 (d, J = 16.1 Hz, 1H),5.52-5.43 (m, 1H), 5.31 (dd, J = 16.1, 8.9 Hz, 1H), 4.01 (d, J = 2.9 Hz,2H), 3.94 (q, J = 7.7 Hz, 1H), 3.83 (td, J = 8.3, 4.6 Hz, 1H), 3.71 (d,J = 10.1 Hz, 2H), 3.43 (d, J = 9.5 Hz, 2H), 2.57-2.46 (m, 1H), 2.44-2.30(m, 1H), 2.22-2.09 (m, 1H), 1.86-1.79 (m, 2H), 1.43 (dt, J = 9.0, 3.2Hz, 1H), 1.26- 0.97 (m, 4H). A2 121

MS (ESI): m/z 533.1 [M + H]⁺; EC₅₀ = 824; ¹H NMR (500 MHz, Methanol-d₄)δ 9.55 (dd, J = 8.8, 1.1 Hz, 1H), 8.77-8.72 (m, 3H), 8.24 (d, J = 8.5Hz, 1H), 7.50 (dd, J = 8.8, 3.9 Hz, 1H), 6.80 (d, J = 8.5 Hz, 1H), 6.17(d, J = 16.0 Hz, 1H), 5.29 (dd, J = 16.0, 8.8 Hz, 1H), 4.52 (d, J = 11.0Hz, 2H), 3.70 (br d, J = 10.7 Hz, 2H), 2.36-2.22 (m, 1H), 1.73 (br s,2H), 1.65-1.55 (m, 1H), 1.25-1.15 (m, 4H). A2 122

MS (ESI): m/z 563.1 [M + H]⁺; EC₅₀ = 126; ¹H NMR (400 MHz, Methanol-d₄)δ 8.72 (s, 2H), 8.05 (s, 1H), 7.77 (d, J = 9.0 Hz, 1H), 7.22 (dd, J =8.9, 2.3 Hz, 1H), 7.10 (s, 1H), 6.15 (d, J = 16.1 Hz, 1H), 5.27 (dd, J =16.1, 8.8 Hz, 1H), 4.16 (s, 3H), 3.72 (d, J = 9.7 Hz, 2H), 3.46-3.39 (m,2H), 2.27 (tt, J = 8.1, 5.4 Hz, 1H), 1.77 (br s, 2H), 1.43 (dt, J = 8.8,3.2 Hz, 1H), 1.26-1.10 (m, 4H). A2 123

MS (ESI): m/z 618.1 [M + H]⁺; EC₅₀ = 206; ¹H NMR (400 MHz, DMSO-d₆) δ8.86 (s, 2H), 8.71 (s, 1H), 8.46 (s, 1H), 8.41 (s, 1H), 6.15 (d, J =16.1 Hz, 1H), 5.30 (dd, J = 16.1, 8.9 Hz, 1H), 3.66 (d, J = 10.3 Hz,2H), 3.56-3.48 (m, 2H), 2.43-2.33 (m, 1H), 1.81-1.68 (m, 2H), 1.41 (dt,J = 8.7, 3.3 Hz, 1H), 1.24-1.05 (m, 4H). H 124

MS (ESI): m/z 570.0 [M + H]⁺; EC₅₀ = 284; ¹H NMR (500 MHz, Methanol-d₄)δ 8.73 (s, 2H), 7.75 (s, 1H), 6.19 (d, J = 16.0 Hz, 1H), 5.29 (dd, J =16.0, 8.5 Hz, 1H), 4.10 (s, 3H), 3.89-3.78 (m, 2H), 3.73 (br d, J = 9.4Hz, 2H), 2.36-2.22 (m, 1H), 1.81 (br s, 2H), 1.47-1.39 (m, 1H),1.24-1.16 (m, 4H). A1 125

MS (ESI) m/z: 565.2 [M + H]⁺; EC₅₀ = 14; ¹H NMR (500 MHz, Methanol-d₄) δ8.92 (br d, J = 4.40 Hz, 1H), 8.34 (d, J = 7.98 Hz, 1H), 8.09-8.24 (m,1H), 7.79-7.92 (m, 1H), 7.75 (br d, J = 2.75 Hz, 2H), 7.41 (br s, 1H),6.19 (d, J = 16.23 Hz, 1H), 5.37-5.48 (m, 1H), 4.31 (br s, 3H), 3.95 (brd, J = 1.93 Hz, 2H). 2.90-3.03 (m, 2H), 2.21-2.33 (m, 2H), 1.77 (br d, J= 12.10 Hz, 2H), 1.33-1.43 (m, 2H), 1.10-1.21 (m, 4H). A2 126

MS (ESI): m/z 605.2 [M + H]⁺; EC₅₀ = 18; ¹H NMR (400 MHz, DMSO-d₆) δ8.80 (s, 2H), 7.88 (d, J = 9.3 Hz, 1H), 7.28 (dd, J = 9.4, 2.7 Hz, 1H),6.96 (s, 1H), 6.89 (d, J = 2.7 Hz, 1H), 6.08 (d, J = 16.1 Hz ,1H), 5.58(q, J = 5.3 Hz, 1H), 5.24 (dd, J = 1.61, 8.9 Hz, 1H), 4.98 (t, J = 6.7Hz, 2H), 4.64 (dd, J = 7.5, 4.5 Hz, 2H), 3.67 (d, J = 10.1 Hz, 2H),3.40-3.30 (m, 2H), 2.31 (tt, J = 8.5, 5.2 Hz, 1H), 1.83- 1.71 (m, 2H),1.37 (dt, J = 8.9, 3.2 Hz, 1H), 1.19-0.96 (m, 4H). A2 127

MS (ESI): m/z 619.2 [M + H]⁺; EC₅₀ = 30; ¹H NMR (400 MHz, DMSO-d₆) δ8.79 (s, 2H), 7.91 (d, J = 9.3 Hz, 1H), 7.35 (s, 1H), 7.29 (dd, J = 9.4,2.8 Hz, 1H), 6.79 (d, J = 2.7 Hz, 1H), 6.07 (d, J = 16.0 Hz, 1H),5.41-5.34 (m, 1H), 5.23 (dd, J = 16.1, 8.9 Hz, 1H), 3.99-3.90 (m, 2H),3.87 (q, J = 7.9 Hz, 1H),3 .75 (td, J = 8.3, 4.6 Hz, 1H), 3.64 (d, J =10.1 Hz, 2H), 3.37-3.31 (m, 2H), 2.36-2.23 (m, 2H), 2.12-2.01 (m, 1H),1.81-1.71 (m, 2H), 1.36 (dt, J = 8.9, 3.3 Hz, 1H), 1.18-0.96 (m, 4H). A2128

MS (ESI): m/z 619.3 [M + H]⁺; EC₅₀ = 27; ¹H NMR (400 MHz, DMSO-d₆) δ8.79 (s, 2H), 7.91 (d, J = 9.3 Hz, 1H), 7.35 (s, 1H), 7.29 (dd, J = 9.3,2.8 Hz, 1H), 6.79 (d, J = 2.7 Hz, 1H), 6.07 (d, J = 16.1 Hz, 1H),5.42-4.35 (m, 1H), 5.23 (dd, J = 16.1, 8.9 Hz, 1H), 3.98-3.90 (m, 2H),3.87 (q, J = 7.9 Hz, 1H), 3.75 (td, J = 8.3, 4.6 Hz, 1H), 3.64 (d, J =10.1 Hz, 2H), 3.35 (d, J = 10.0 Hz, 2H), 2.36-2.20 (m, 2H), 2.13-2.00(m, 1H), 1.81-1.68 (m, 2H), 1.36 (dt, J = 9.0, 3.2 Hz, 1H), 1.21-0.91(m, 4H). A2 129

MS (ESI) m/z: 669.3 [M + H]⁺; EC₅₀ = 240; ¹H NMR (500 MHz, DMSO-d₆) δ8.83 (s, 2H), 7.93- 8.02 (m, 1H), 7.46 (br d, J = 8.24 Hz, 2H),7.28-7.36 (m, 1H), 6.98 (br d, J = 8.54 Hz, 2H), 6.07-6.18 (m, 1H), 5.39(s, 2H), 5.20-5.31 (m, 1H), 3.88 (s, 1H), 3.76 (s, 3H), 3.64 (br d, J =10.07 Hz, 1H), 3.37 (br d, J = 8.54 Hz, 1H), 2.30-2.38 (m, 1H), 1.78 (brs, 2H), 1.37-1.43 (m, 1H), 1.15-2.0 (m, 2H), 1.08 (br d, J = 2.44 Hz,2H) additional signals were lost due to water suppression. A2 130

MS (ESI) m/z: 602.2 [M + H]⁺; EC₅₀ = 50; ¹H NMR (400 MHz, Methanol-d₄) δ8.13 (d, J = 9.46 Hz, 1H), 7.86-7.91 (m, 1H), 7.68-7.80 (m, 2H),7.51-7.57 (m, 2H), 7.45 (d, J = 6.82 Hz, 1H), 7.03 (d, J = 2.64 Hz, 1H),6.04-6.16 (m, 1H), 5.28 (t, J = 7.26 Hz, 1H), 3.75 (d, J = 9.90 Hz, 2H),3.46-3.55 (m, 2H), 2.66-2.76 (m, 2H), 2.36-2.48 (m, 2H), 2.20-2.28 (m,1H), 1.97-2.07 (m, 1H), 1.86-1.96 (m, 1H), 1.76 (br s, 2H), 1.33-1.40(m, 2H), 1.11-1.20 (m, 4H). A2 131

MS (ESI): m/z 580.1 [M + H]⁺; EC₅₀ = 73; ¹H NMR (400 MHz, Methanol-d₄) δ8.62 (s, 2H), 8.14 (t, J = 1.4 Hz, 1H), 7.76-7.51 (m, 2H), 6.05 (d, J =15.9 Hz, 1H), 5.16 (dd, J = 16.0, 8.7 Hz, 1H), 3.83 (s, 3H), 3.63 (d, J= 10.2 Hz, 2H), 3.45-3.39 (m, 2H), 2.21-2.10 (m, 1H), 1.63-1.55 (m, 2H),1.35-1.26 (m, 1H), 1.16-0.99 (m, 4H). H 132

MS (ESI) m/z: 562.2 [M + H]⁺; EC₅₀ = 16; ¹H NMR (400 MHz, DMSO-d₆) δ8.02 (d, J = 9.24 Hz, 1H), 7.92 (d, J = 7.48 Hz, 1H), 7.73-7.85 (m, 2H),7.47-7.54 (m, 2H), 7.37 (dd, J = 2.53, 9.35 Hz, 1H), 6.83 (d, J = 2.42Hz, 1H), 6.07 (d, J = 16.07 Hz, 1H), 5.17 (dd, J = 8.91, 16.18 Hz, 1H),4.14 (s, 3H), 3.66 (d, J = 9.90 Hz, 2H), 3.39 (br d, J = 9.24 Hz, 2H),2.31 (s, 1H), 1.72 (br s, 2H), 1.32-1.39 (m, 1H), 1.10-1.18 (m, 2H),1.06 (dd, J = 2.20, 5.06 Hz, 2H). A2 133

MS (ESI): m/z 550.2 [M + H]⁺; EC₅₀ = 1292; ¹H NMR (500 MHz, DMSO-d6) δ8.86 (s, 2H), 8.44 (t, J = 1.8 Hz, 1H), 8.10 (ddt, J = 10.9, 7.8, 1.4Hz, 2H), 7.65 (t, J = 7.8 Hz, 1H), 6.14 (d, J = 16.0 Hz, 1H), 5.32 (dd,J = 16.1, 8.8 Hz, 1H), 3.76 (d, J = 10.5 Hz, 2H), 3.70 (dt, J = 10.5,1.8 Hz, 2H), 2.38 (tt, J = 8.6, 5.2 Hz, 1H), 1.83-1.78 (m, 2H), 1.46(dt, J = 8.7, 3.4 Hz, 1H), 1.26-1.01 (m, 4H). I 134

MS (ESI) m/z: 604.2 [M + H]⁺; EC₅₀ = 15; ¹H NMR (500 MHz, Methanol-d₄) δ8.14 (br d, J = 8.53 Hz, 1H), 7.88 (d, J = 7.70 Hz, 1H), 7.70-7.79 (m,2H), 7.55 (br d, J = 9.08 Hz, 1H), 7.45 (br d, J = 7.15 Hz, 1H), 7.28(s, 1H), 7.10 (br s, 1H), 6.06-6.14 (m, 1H), 5.82 (br s, 1H), 5.15- 5.26(m, 3H), 4.90 (br dd, J = 4.54, 7.29 Hz, 2H), 3.76 (br d, J = 10.18 Hz,2H), 3.52 (br d, J = 9.08 Hz, 2H), 2.22 (br s, 1H), 1.75 (br s, 2H),1.34-1.39 (m, 1H), 1.10-1.19 (m, 4H). A2 135

MS (ESI) m/z: 562.2 [M + H]⁺; EC₅₀ = 416; ¹H NMR (500 MHz, DMSO-d₆) δ8.04 (s, 1H), 7.93 (br d, J = 7.70 Hz, 1H), 7.87 (d, J = 9.08 Hz, 1H),7.79-7.84 (m, 1H), 7.78 (br d, J = 7.70 Hz, 1H), 7.52 (br d, J = 7.43Hz, 1H), 7.22 (br d, J = 7.70 Hz, 1H), 6.93 (s, 1H), 6.03-6.11 (m, 1H),5.17 (dd, J = 8.94, 16.09 Hz, 1H), 4.07 (s, 3H), 3.65 (br d, J = 9.90Hz, 2H), 3.37 (br d, J = 8.80 Hz, 2H), 2.31 (br d, J = 4.95 Hz, 1H),1.71 (br s, 2H), 1.30-1.39 (m, 1H), 1.11- 1.18 (m, 2H), 1.06 (br d, J =2.48 Hz, 2H). A2 136

MS (ESI): m/z 603.2 [M + H]⁺; EC₅₀ = 20; ¹H NMR (400 MHz, Methanol-d₄) δ8.72 (s, 2H), 8.28-7.99 (m, 1H), 7.62-7.34 (m, 2H), 7.02 (br s, 1H),6.15 (d, J = 16.1 Hz, 1H), 5.28 (dd, J = 16.1, 8.8 Hz, 1H), 3.75 (d, J =10.1 Hz, 2H), 3.48 (td, J = 3.4, 2.0 Hz, 2H), 3.13 (dt, J = 3.2, 1.6 Hz,1H), 2.76-2.67 (m, 2H), 2.44-2.33 (m, 2H), 2.31-2.22 (m, 1H), 1.81 (brs, 2H), 1.46-1.40 (m, 1H), 1.29 (br s, 2H), 1.22- 1.16 (m, 4H). A2 137

MS (ESI): m/z 622.3 [M + H]⁺; EC₅₀ = 932; ¹H NMR (400 MHz, CDCl₃) δ 8.66(s, 2H), 8.41 (s, 1H), 7.63 (s, 1H), 7.57 (s, 1H), 6.04 (d, J = 15.9 Hz,1H), 5.42-5.31 (m, 1H), 5.24 (dd, J = 16.0, 8.7 Hz, 1H), 5.11-5.00 (m,2H), 4.87-4.76 (m, 2H), 3.81 (d, J = 10.3 Hz, 2H), 3.55 (d, J = 10.0 Hz,2H), 2.21-2.06 (m, 1H), 1.69-1.61 (m, 2H), 1.44- 1.37 (m, 1H), 1.22-0.72(m, 4H). H 138

MS (ESI) m/z: 533.2 [M + H]⁺; EC₅₀ = 2470; ¹H NMR (400 MHz, Methanol-d₄)δ 9.07 (s, 1H), 7.84-7.94 (m, 2H), 7.67-7.81 (m, 2H), 7.41-7.54 (m, 2H),6.98 (br s, 1H), 6.02-6.17 (m, 1H), 5.20 (dd, J = 8.80, 16.07 Hz, 1H),3.75 (d, J = 10.12 Hz, 2H), 3.46-3.56 (m, 2H), 2.23 (s, 1H), 1.73 (br s,2H), 1.35-1.42 (m, 1H), 1.08-1.22 (m, 4H). A2 139

MS (ESI): m/z 569.2 [M + H]⁺; EC₅₀ = 163; ¹H NMR (500 MHz, Methanol-d₄)δ 7.89 (d, J = 7.4 Hz, 1H), 7.79-7.71 (m, 3H), 7.46 (d, J = 7.4 Hz, 1H),6.14 (d, J = 16.2 Hz, 1H), 5.20 (dd, J = 16.0, 8.5 Hz, 1H), 4.09 (s,3H), 3.81 (br s, 2H), 3.71 (br d, J = 10.2 Hz, 2H), 2.24 (br s, 1H),1.73 (br s, 2H), 1.39-1.30 (m, 1H), 1.21-1.11 (m, 4H). A1 140

MS (ESI) m/z: 533.2 [M + H]⁺; EC₅₀ = 142; ¹H NMR (400 MHz, Methanol-d₄)δ 9.19 (s, 1H), 7.96 (br d, J = 9.02 Hz, 1H), 7.83-7.90 (m, 1H),7.66-7.79 (m, 2H), 7.39-7.48 (m, 2H), 6.85 (d, J = 2.64 Hz, 1H),6.04-6.14 (m, 1H), 5.21 (d, J = 8.80 Hz, 1H), 3.76 (d, J = 10.56 Hz,2H), 3.55 (dd, J = 1.76, 8.36 Hz, 2H), 2.17-2.26 (m, 1H), 1.74 (br s,2H), 1.32-1.39 (m, 1H), 1.10-1.19 (m, 4H). A2 141

MS (ESI): m/z 563.3 [M + H]⁺; EC₅₀ = 98; ¹H NMR (400 MHz, DMSO-d₆) δ8.93 (dd, J = 4.7, 1.5 Hz, 1H), 8.09 (dd, J = 7.9, 1.5 Hz, 1H), 8.03 (d,J = 9.5 Hz, 1H), 7.89 (dd, J = 7.9, 4.8 Hz, 1H), 7.51 (s, 1H), 7.40 (dd,J = 9.4, 2.7 Hz, 1H), 6.85 (d, J = 2.7 Hz, 1H), 6.12 (d, J = 16.1 Hz,1H), 5.25 (dd, J = 16.1, 8.9 Hz, 1H), 4.15 (s, 3H), 3.68 (d, J = 10.0Hz, 2H), 3.45-3.33 (m, 2H), 2.40-2.21 (m, 1H), 1.82-1.73 (m, 2H), 1.41(dt, J = 9.1, 3.2 Hz, 1H), 1.31-0.95 (m, 4H). A2 142

MS (ESI): m/z 603.3 [M + H]⁺; EC₅₀ = 54; ¹H NMR (400 MHz, DMSO-d₆) δ8.93 (dd, J = 4.7, 1.5 Hz, 1H), 8.09 (dd, J = 8.0, 1.6 Hz, 1H), 8.03 (d,J = 9.3 Hz, 1H), 7.90 (dd, J = 7.9, 4.7 Hz, 1H), 7.40 (dd, J = 9.4, 2.7Hz, 1H), 7.31 (s, 1H), 6.87 (d, J = 2.6 Hz, 1H), 6.11 (d, J = 16.1 Hz,1H), 5.26 (dd, J = 16.1, 8.9 Hz, 1H), 5.15 (p, J = 7.2 Hz, 1H), 3.70 (d,J = 10.1 Hz, 2H), 3.48-3.39 (m, 2H), 2.62-2.42 (m, 2H), 2.38-2.39 (m,1H), 2.30-2.18 (m, 2H), 1.97-1.6 (m, 4H), 1.40 (dt, J = 8.9, 3.2 Hz,1H), 1.25- 1.00 (m, 4H). A2 143

MS (ESI): m/z 605.3 [M + H]⁺; EC₅₀ = 88; ¹H NMR (400 MHz, DMSO-d₆) δ8.86 (dd, J = 4.7, 1.6 Hz, 1H), 8.02 (dd, J = 7.9, 1.5 Hz, 1H), 7.89 (d,J = 9.3 Hz, 1H), 7.82 (dd, J = 7.9, 4.8 Hz, 1H), 7.28 (dd, J = 9.3, 2.7Hz, 1H), 6.96 (s, 1H), 6.89 (d, J = 2.7 Hz, 1H), 6.05 (d, J = 16.0 Hz,1H), 5.59 (p, J = 5.2 Hz, 1H), 5.18 (dd, J = 16.1, 8.9 Hz, 1H),5.04-4.90( m, 2H), 4.64 (dd, J = 7.6, 4.5 Hz, 2H), 3.65 (d, J = 10.1 Hz,2H), 3.41-3.27 (m, 2H), 2.33-2.21 (m, 1H), 1.78-1.64 (m, 2H), 1.34 (dt,J = 8.9, 3.2 Hz, 1H), 1.18-0.88 (m, 4H). A2 144

MS (ESI) m/z: 482.1 [M + H]⁺; EC₅₀ = 424; ¹H NMR (500 MHz, DMSO-d₆) δ8.58 (d, J = 1.8 Hz, 1H), 7.90 (dd, J = 9.0, 2.0 Hz, 1H), 7.70-7.63(m,2H), 7.63-7.56 (m, 1H), 7.28-7.99 (m, 1H), 6.47 (d, J = 9.2 Hz, 1H),6.14 (d, J = 15.9 Hz, 1H), 5.15 (dd, J = 16.0, 9.0 Hz, 1H), 3.82-3.66(m, 1H), 2.42-2.26 (m, 1H), 1.69 (br s, 2H), 1.37-1.29 (m, 1H), 1.22-1.14 (m, 2H), 1.12-1.02 (m, 2H) additional signals were lost due towater suppression. A1 145

MS (ESI) m/z: 588.3 [M + H]⁺; EC₅₀ = 419; ¹H NMR (500 MHz, DMSO-d₆) δ8.32 (br s, 1H), 7.29-7.92 (m, 6H), 6.48-6.64 (m, 1H), 6.13-6.24 (m,1H), 5.35-5.52 (m, 1H), 2.99 (br s, 2H), 2.34 (br dd, J = 4.27, 8.85 Hz,1H), 2.05-2.14 (m, 1H), 1.68 (br s, 1H), 1.13-1.18 (m, 2H), 1.07 (br d,J = 2.44 Hz, 2H) additional signals were lost due to water suppression.A2 146

MS (ESI) m/z: 588.4 [M + H]⁺; EC₅₀ = 22; ¹H NMR (500 MHz, DMSO-d₆) δ8.15 (br s, 1H), 8.03 (br s, 1H), 7.78 (br d, J = 7.63 Hz, 1H), 7.70 (brd, J = 7.63 Hz, 1H), 7.61 (br d, J = 7.32 Hz, 1H), 7.47 (br d,J = 7.32Hz, 1H), 7.37 (br d, J = 6.10 Hz, 1H), 6.58 (br s, 1H), 6.17 (br d, J =16.17 Hz, 1H), 5.37-5.49 (m, 1H), 2.98 (br d, J = 4.58 Hz, 2H), 2.32 (brd, J = 4.27 Hz, 1H), 2.04-2.13 (m, 1H), 1.62-1.72 (m, 1H), 1.12 (br d, J= 7.93 Hz, 2H), 1.04 (br s, 2H) additional signals were lost due towater suppression. A2 147

MS (ESI) m/z: 590.2 [M + H]⁺; EC₅₀ = 139; ¹H NMR (400 MHz, Methanol-d₄)δ 8.11 (br d, J = 9.24 Hz, 1H), 7.78 (d, J = 7.70 Hz, 1H), 7.66-7.72 (m,1H), 7.57-7.64 (m, 1H), 7.51 (s, 1H), 7.42-7.47 (m, 1H), 6.88-6.97 (m,1H), 6.23 (d, J = 16.07 Hz, 1H), 5.49-5.60 (m, 1H), 5.27 (br t, J = 7.15Hz, 1H), 3.58 (br s, 1H), 3.43 (br t, J = 6.71 Hz, 2H), 3.08 (br d, J =5.72 Hz, 2H), 2.67-2.78 (m, 2H), 2.42 (ddd, J = 2.64, 7.43, 9.96 Hz,2H), 2.16-2.30 (m, 2H),1 .98-2.07 (m, 1H), 1.86-1.97 (m, 1H), 1.80 (brdd, J = 8.14, 12.32 Hz, 1H), 1.12-1.22 (m, 5H). A2 148

MS (ESI) m/z: 590.2 [M + H]⁺; EC₅₀ = 2; ¹H NMR( 400 MHz, Methanol-d₄) δ8.11 (d, J = 9.46 Hz, 1H), 7.79 (d, J = 7.92 Hz, 1H), 7.70 (s, 1H),7.57-7.65 (m, 1H), 7.41-7.50 (m, 2H), 6.93 (d, J = 2.42 Hz, 1H), 6.23(d, J = 16.07 Hz, 1H), 5.49- 5.60 (m, 1H),5.27 (br t, J = 7.15 Hz, 1H),3.59 (br d, J = 1.76 Hz, 1H), 3.43 (br dd, J = 5.94, 7.70 Hz, 2H),3.03-3.11 (m, 2H), 2.68-2.78 (m, 2H), 2.42 (br s, 2H), 2.16- 2.31 (m,2H), 1.98-2.08 (m, 1H), 1.87-1.98 (m, 1H), 1.74-1.86 (m, 1H), 1.17 (dtd,J = 2.42, 5.45, 11.11 Hz, 5H). A2 149

MS (ESI) m/z: 564.2 [M + H]⁺; EC₅₀ = 164; ¹H NMR (500 MHz, Methanol-d₄)δ 8.14 (br d, J = 9.1 Hz, 1H), 7.90 (d, J = 7.7 Hz, 1H), 7.81-7.76 (m,1H), 7.75-7.69 (m, 2H), 7.49 (br d, J = 7.7 Hz, 1H), 7.30 (br d, J = 8.5Hz, 1H), 6.89 (s, 1H), 6.25 (d, J = 16.0 Hz, 1H), 5.81 (dd, J = 16.1,8.4 Hz, 1H), 5.26 (dt, J = 12.0, 5.8 Hz, 1H), 4.27 (br t, J = 7.8 Hz,2H), 3.72 (br t, J = 6.6 Hz, 2H), 3.59-3.50 (m, 1H), 2.35-2.27 (m, 1H),1.59 (d, J = 6.1 Hz, 6H), 1.25- 1.14 (m, 4H). A2 150

MS (ESI) m/z: 576.3 [M + H]⁺; EC₅₀ = 58; ¹H NMR (500 MHz, Methanol-d₄) δ8.13 (br d, J = 8.8 Hz, 1H), 7.90 (d, J = 7.7 Hz, 1H), 7.78 (t, J = 7.7Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H), 7.54 (s, 1H), 7.50 (d, J = 7.5 Hz,1H), 7.29 (br d, J = 8.8 Hz, 1H), 6.90 (s, 1H), 6.26 (d, J = 16.0 Hz,1H), 5.82 (dd, J = 16.0, 8.3 Hz, 1H), 5.26 (quin, J = 7.0 Hz, 1H), 4.28(br t, J = 7.7 Hz, 2H), 3.72 (br t, J = 6.3 Hz, 2H), 3.58-3.51 (m, 1H),2.77-2.68 (m, 2H), 2.47-2.37 (m, 2H), 2.34- 2.25 (m, 1H), 2.03 (q, J =10.3 Hz, 1H), 1.96-1.87 (m, 1H), 1.24-1.14 (m, 4H). A2 151

MS (ESI) m/z: 578.3 [M + H]⁺; EC₅₀ = 96; ¹H NMR (500 MHz, DMSO-d₆) δ11.82 (br s, 1H), 7.95 (br d, J = 9.1 Hz, 1H), 7.79 (br d, J = 7.2 Hz,1H), 7.73- 7.58 (m, 2H), 7.48 (br d, J = 7.2 Hz, 1H), 7.21 (br d, J =8.5 Hz, 1H), 7.03 (s, 1H), 6.95 (br s, 1H), 6.71 (br s, 1H), 5.64 (br s,1H), 5.05 (br t, J = 5.8 Hz, 2H), 4.71 (br s, 2H), 4.42 (br s, 2H), 4.07(br s, 4H), 2.14-2.06 (m, 1H), 0.78-0.57 (m, 4H). A2 152

MS (ESI) m/z: 612.4 [M + H]⁺; EC₅₀ = 228; ¹H NMR (500 MHz, Methanol-d₄)δ 8.13 (br d, J = 9.1 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.81-7.75 (m,1H), 7.75-7.70 (m, 1H), 7.53 (s, 1H), 7.49 (d, J = 7.4 Hz, 1H), 7.26 (brd, J = 8.8 Hz, 1H), 6.91 (d, J = 1.4 Hz, 1H), 6.25 (d, J = 16.2 Hz, 1H),5.81 (dd, J = 16.1, 8.4 Hz, 1H), 5.25 (br s, 1H), 4.27 (t, J = 7.8 Hz,2H), 3.71 (br t, J = 6.7 Hz, 2H), 3.58-3.50 (m, 1H), 3.45-3.38 (m, 2H),3.09-2.97 (m, 2H), 2.35-2.26 (m, 1H), 1.25-1.15 (m, 4H). A2 153

MS (ESI) m/z: 543.3 [M + H]⁺; EC₅₀ = 473; ¹H NMR (500 MHz, Methanol-d₄)δ 7.89 (d, J = 7.7 Hz, 1H), 7.80-7.75 (m, 2H), 7.75-7.70 (m, 1H), 7.49(d, J = 7.4 Hz, 1H), 6.25 (d, J = 16.0 Hz, 1H), 5.81 (br dd, J = 15.8,8.4 Hz, 1H), 4.40 (br t, J = 8.4 Hz, 2H), 4.09 (s, 3H), 3.89 (br t, J =6.9 Hz, 2H), 3.65-3.57 (m, 1H), 2.36-2.28 (m, 1H), 1.25-1.14 (m, 4H). A1154

MS (ESI) m/z: 536.3 [M + H]⁺; EC₅₀ = 63; ¹H NMR (500 MHz, Methanol-d₄) δ8.13 (d, J = 9.4 Hz, 1H), 7.89 (d, J = 7.7 Hz, 1H), 7.80-7.75 (m, 1H),7.74- 7.70 (m, 2H), 7.49 (d, J = 7.4 Hz, 1H), 7.28 (dd, J = 9.1, 2.5 Hz,1H), 6.92 (d, J = 2.5 Hz, 1H), 6.25 (d, J = 16.0 Hz, 1H), 5.81 (dd, J =16.1, 8.4 Hz, 1H), 4.33 (s, 3H), 4.26 (t, J = 7.8 Hz, 2H), 3.74-3.67 (m,2H), 3.58-3.50 (m, 1H), 2.35-2.26 (m, 1H), 1.25-1.15 (m, 4H). A2 155

EC₅₀ = 784; H NMR (400 MHz, DMSO-d₆) δ 13.48 (s, 1H), 8.92 (dd, J = 4.8,1.5 Hz, 1H), 8.13-8.05 (m, 2H), 7.89 (dd, J = 7.9, 4.7 Hz, 1H), 7.68 (d,J = 1.5 Hz, 2H), 6.12 (d, J = 16.1 Hz, 1H), 5.24 (dd, J = 16.1, 8.9 Hz,1H), 3.91 (s, 3H), 3.62 (d, J = 10.2 Hz, 2H), 3.46 (dt, J = 10.1, 2.0Hz, 2H), 2.33 (tt, J = 8.3, 5.1 Hz, 1H), 1.69 (d, J = 3.2 Hz, 2H), 1.38(dt, J = 8.9, 3.3 Hz, 1H), 1.30-0.83 (m, 4H). H 156

MS (ESI) m/z: 577.5 [M + H]⁺; EC₅₀ = 43; ¹H NMR (400 MHz, DMSO-d₆) δ8.86 (dd, J = 4.8, 1.5 Hz, 1H), 8.02 (dd, J = 7.9, 1.5 Hz, 1H), 7.95 (d,J = 9.3 Hz, 1H), 7.82 (dd, J = 7.9, 4.7 Hz, 1H), 7.40 (s, 1H), 7.32 (dd,J = 9.4, 2.7 Hz, 1H), 6.79 (d, J = 2.6 Hz, 1H), 6.04 (d, J = 16.1 Hz,1H), 5.18 (dd, J = 16.1, 8.9 Hz, 1H), 4.36 (q, J = 7.0 Hz, 2H), 3.61 (d,J = 10.1 Hz, 2H), 3.47-3.15 (m, 2H), 2.26 (ddt, J = 10.1, 8.2, 4.2 Hz,1H), 1.71 (d, J = 3.1 Hz, 2H), 1.42 (t, J = 7.0 Hz, 3H), 1.33 (dt, J =9.0, 3.2 Hz, 1H), 1.17-1.05 (m, 2H), 1.05-0.92 (m, 2H). A2 157

MS (ESI) m/z: 619.5 [M + H]⁺; EC₅₀ = 165; ¹H NMR (400 MHz, DMSO-d₆) δ8.86 (dd, J = 4.8, 1.5 Hz, 1H), 8.02 (dd, J = 7.9, 1.5 Hz, 1H), 7.97 (d,J = 9.4 Hz, 1H), 7.82 (dd, J = 7.9, 4.7 Hz, 1H), 5.39 (s, 1H), 7.33 (dd,J = 9.4, 2.7 Hz, 1H), 6.79 (d, J = 2.7 Hz, 1H), 6.03 (d, J = 16.1 Hz,1H), 5.48- 5.39 (m, 1H), 5.18 (dd, J = 16.1, 8.9 Hz, 1H), 3.94 (d, J =3.0 Hz, 2H), 3.87 (q, J = 7.9 Hz, 1H), 3.76 (td, J = 8.3, 4.7 Hz, 1H),3.62 (d, J = 10.1 Hz, 2H), 3.45-3.28 (m, 2H), 2.38-2.17 (m, 2H),2.13-2.02 (m, 1H), 1.75-1.68 (m, 2H), 1.32 (dt, J = 9.0, 3.2 Hz, 1H),1.19-1.05 (m, 2H), 1.05-0.94 (m, 2H). A2 158

MS (ESI) m/z: 525.2 [M + H]⁺; EC₅₀ = 555; ¹H NMR (500 MHz, Methanol-d₄)δ 7.87 (d, J = 7.70 Hz, 1H), 7.69-7.78 (m, 2H), 7.53 (d, J = 2.20 Hz,1H), 7.44 (d, J = 7.15 Hz, 1H), 6.42-6.45 (m, 1H), 6.08 (d, J = 16.23Hz, 1H), 5.18 (dd, J = 8.80, 15.96 Hz, 1H), 4.17 (q, J = 7.15 Hz, 2H),3.62 (d, J = 10.18 Hz, 2H), 3.43 (br d, J = 9.90 Hz, 2H), 2.18-2.25 (m,1H), 1.70 (br s, 2H), 1.44 (t, J = 702 Hz, 3H), 1.27-1.41 (m, 1H),1.10-1.19 (m, 4H). A2 159

MS (ESI) m/z: 577.2 [M + H]⁺; EC₅₀ = 39; ¹H NMR (500 MHz, Methanol-d₄) δ8.68 (s, 2H), 8.06-8.16 (m, 1H), 7.52 (s, 1H), 7.27 (br d, J = 7.70 Hz,1H), 6.89 (d, J = 2.20 Hz, 1H), 6.28 (d, J = 15.96 Hz, 1H), 5.84 (dd, J= 8.25, 15.96 Hz, 1H), 5.23 (s, 1H), 4.31 (s, 2H), 3.79 (br t, J = 6.74Hz, 2H), 3.59 (br d, J = 7.70 Hz, 1H), 2.66-2.76 (m, 2H), 2.41 (br s,2H), 2.25-2.33 (m, 1H), 2.03 (s, 1H), 1.89 (br d, J = 10.18 Hz, 1H),1.15-1.28 (m, 4H). A2 160

MS (ESI) m/z: 579.2 [M + H]⁺; EC₅₀ = 65; ¹H NMR (500 MHz, Methanol-d₄) δ8.64 (s, 2H), 8.08 (br d, J = 7.98 Hz, 1H), 7.22 (br s, 1H), 7.14-7.20(m, 1H), 6.92 (br s, 1H), 6.21 (br d, J = 15.13 Hz, 1H), 5.79- 5.87 (m,1H), 5.69 (br s, 1H), 5.20 (br s, 2H), 4.88 (br s, 2H), 4.30 (br s, 2H),3.78 (br s, 2H), 3.57 (br s, 1H), 2.17-2.24 (m, 1H), 1.22 (br s, 4H). A2161

MS (ESI) m/z: 534.1 [M + H]⁺; EC₅₀ = 192; ¹H NMR (500 MHz, Methanol-d₄)δ 9.22 (s, 1H), 8.66 (s, 2H), 7.98 (br d, J = 9.46 Hz, 1H), 7.69 (s,1H), 7.37 (dd, J = 2.64, 9.46 Hz, 1H), 6.85 (d, J = 2.20 Hz, 1H), 6.08(d, J = 15.85 Hz, 1H), 5.29 (dd, J = 8.58, 16.07 Hz, 1H), 3.79 (d, J =10.34 Hz, 2H), 3.59 (br d, J = 10.12 Hz, 2H), 2.15-2.24 (m, 1H), 1.82(br s, 2H), 1.35-1.45 (m, 1H), 1.19 (d, J = 6.82 Hz, 4H). A2 162

MS (ESI) m/z: 575.1 [M + H]⁺; EC₅₀ = 150; ¹H NMR (400 MHz, Methanol-d₄)δ 8.71 (s, 2H), 8.28 (s, 1H), 8.09 (d, J = 9.24 Hz, 1H), 7.19 (dd, J=2.42, 9.24 Hz, 1H), 6.63 (s, 1H), 6.30 (dd, J = 0.88, 16.07 Hz, 1H),5.90 (dd, J = 8.14, 16.07 Hz, 1H), 4.29 (t, J = 8.03 Hz, 2H), 3.78 (dd,J = 5.94, 7.92 Hz, 2H), 3.52-3.62 (m, 1H), 2.30-2.37 (m, 1H), 1.13-1.28(m, 4H). A2 163

MS (ESI) m/z: 526.2 [M + H]⁺; EC₅₀ = 424; ¹H NMR (500 MHz, Methanol-d₄)δ 8.29 (s, 1H), 7.87 (br d, J = 7.43 Hz, 1H), 7.68-7.79 (m, 2H), 7.44(br d, J = 7.15 Hz, 1H), 6.18 (s, 1H), 6.10 (d, J = 15.96 Hz, 1H), 5.22(dd, J = 8.80, 15.96 Hz, 1H), 4.29 (q, J = 6.88 Hz, 2H), 3.78 (br d, J =10.73 Hz, 2H), 3.68-3.75 (m, 2H), 2.21 (br t, J = 4.95 Hz, 1H), 1.84 (brs, 2H), 1.49 (t, J = 7.02 Hz, 3H), 1.34-1.39 (m, 1H), 1.11-1.19 (m, 4H).A2 164

MS (ESI) m/z: 581.3 [M + H]⁺; EC₅₀ = 297; ¹H NMR (400 MHz, DMSO-d₆) δ8.78 (s, 2H), 8.00 (d, J = 1.2 Hz, 1H), 7.45 (d, J = 1.2 Hz, 1H), 6.07(d, J = 16.1 Hz, 1H), 5.22 (dd, J = 16.1, 8.9 Hz, 1H), 3.92 (s, 3H),3.56 (d, J = 10.2 Hz, 2H), 3.41 (dt, J = 10.1, 1.9 Hz, 2H), 2.34-2.27(m, 1H), 1.73-1.61 (m, 2H), 1.33 (dt, J = 8.8, 3.3 Hz, 1H), 1.18- 1.06(m, 2H), 1.06-0.98 (m, 2H). H 165

MS (ESI) mz: 582.3 [M + H]⁺; EC₅₀ = 222; ¹H NMR (400 MHz, DMSO-d₆) δ8.80 (s, 2H), 8.04 (t, J = 1.5 Hz, 1H), 7.64 (dd, J = 2.6, 1.5 Hz, 1H),7.61 (dd, J = 2.7, 1.4 Hz, 1H), 6.12 (dd, J = 16.4, 1.3 Hz, 1H), 5.37(dd, J = 16.3, 6.8 Hz, 1H), 3.84 (s, 3H), 3.83-3.75 (m, 2H), 2.91 (td, J= 12.6, 2.7 Hz, 2H), 2.32 (tt, J = 8.3, 5.1 Hz, 1H), 2.25-2.12 (m, 1H),1.68-1.44 (m, 2H), 1.28-1.06 (m, 4H), 1.06-0.99 (m, 2H). H 166

MS (ESI) m/z: 537.1 [M + H]⁺; EC₅₀ = 29; ¹H NMR (500 MHz, Methanol-d₄) δ8.62 (s, 2H), 8.06 (s, 1H), 7.68 (s, 1H), 7.16 (br d, J = 8.25 Hz, 1H),6.88 (br s, 1H), 6.18 (br d, J = 15.96 Hz, 1H), 5.80 (dd, J = 8.25,15.96 Hz, 1H), 4.20-4.33 (m, 5H), 3.75 (br t, J = 6.46 Hz, 2H), 3.56 (brd, J = 6.88 Hz, 1H), 2.11-2.22 (m, 1H), 1.18-1.25 (m, 4H). A2 167

MS (ESI) m/z: 508.2 [M + H]⁺; EC₅₀ = 308; ¹H NMR (400 MHz, Methanol-d₄)δ 9.21 (s, 1H), 8.72 (s, 2H), 7.98 (d, J = 9.24 Hz, 1H), 7.22 (dd, J=2.64, 9.24 Hz, 1H), 6.68 (d, J = 2.42 Hz, 1H), 6.32 (dd, J = 0.88,16.07 Hz, 1H), 5.92 (d, J = 8.36 Hz, 1H), 4.35 (t, J = 8.47 Hz, 2H),3.85 (dd, J = 6.05, 8.47 Hz, 2H), 3.60 (br d, J = 7.48 Hz, 1H),2.30-2.40 (m, 1H), 1.16-1.25 (m, 4H). A2 168

MS (ESI) m/z: 580.3 [M + H]⁺; EC₅₀ = 1101; ¹H NMR (400 MHz, DMSO-d₆) δ8.86 (s, 2H), 8.06 (dd, J = 7.8, 1.8 Hz, 1H), 7.95 (dd, J = 7.7, 1.8 Hz,1H), 7.39 (t, J = 7.7 Hz, 1H), 6.16 (d, J = 16.0 Hz, 1H), 5.29 (dd, J =16.1, 8.9 Hz, 1H), 3.82 (s, 3H), 3.63 (d, J = 10.2 Hz, 2H), 3.47 (dt, J= 10.0, 1.9 Hz, 2H), 2.44-2.26 (m, 1H), 1.79-1.68 (m, 2H), 1.43 (dt, J =8.9, 3.3 Hz, 1H), 1.27-0.95 (m, 4H). H 169

MS (ESI) m/z: 537.2 [M + H]⁺; EC₅₀ = 223; ¹H NMR (400 MHz, Methanol-d₄)δ 8.83 (dd, J = 1.10, 4.84 Hz, 1H), 8.10 (d, J = 9.24 Hz, 1H), 7.98 (dd,J = 1.10, 7.92 Hz, 1H), 7.78 (dd, J = 4.73, 7.81 Hz, 1H), 7.71 (s, 1H),7.28 (dd, J = 2.53, 9.35 Hz, 1H) ,6.86 (d, J = 2.42 Hz, 1H), 6.25 (dd, J= 0.88, 16.07 Hz, 1H), 5.83 (dd, J = 8.36, 16.07 Hz, 1H), 4.32 (s, 3H),4.26 (t, J = 8.03 Hz, 2H), 3.74 (dd, J = 5.94, 7.92 Hz, 2H), 3.48-3.62(m, 1H), 2.25-2.34 (m, 1H), 1.12-1.24 (m, 4H). A2 170

MS (ESI) m/z: 577.2 [M + H]⁺; EC₅₀ = 50; ¹H NMR (400 MHz, Methanol-d₄) δ8.83 (br s, 1H), 7.93-8.18 (m, 2H), 7.79 (br s, 1H), 7.48 (br s, 1H),7.23 (br s, 1H), 6.78 (br s, 1H), 6.25 (br d, J = 15.85 Hz, 1H), 5.85(br s, 1H), 5.22 (br s, 1H), 4.24 (br s, 2H), 3.72 (br s, 2H), 3.46-3.64(m, 1H), 2.70 (br s, 2H), 2.39 (br s, 2H), 2.18-2.35 (m, 1H), 1.81-2.09(m, 2H), 1.06-1.29 (m, 4H). A2 171

MS (ESI) m/z: 551.2 [M + H]⁺; EC₅₀ = 65; ¹H NMR( 400 MHz, Methanol-d₄) δ8.84 (br d, J = 4.18 Hz, 1H), 8.24 (s, 1H), 8.13 (br d, J = 8.80 Hz,1H), 7.99 (br d, J = 7.70 Hz, 1H), 7.79 (dd, J = 4.73, 7.81 Hz, 1H),7.19-7.26 (m, 1H), 6.59 (d, J = 1.98 Hz, 1H), 6.22-6.31 (m, 1H),5.81-5.89 (m, 1H), 4.94 (s, 2H), 4.28 (t, J = 8.03 Hz, 2H), 3.76 (br t,J = 6.82 Hz, 2H), 3.58 (s, 4H), 2.30 (s, 1H), 1.11-1.26 (m, 4H). A2 172

MS (ESI) m/z: 539.3 [M + H]⁺; EC₅₀ = 29; ¹H NMR (400 MHz, Methanol-d₄) δ7.99 (br d, J = 9.2 Hz, 1H), 7.77 (d, J = 7.7 Hz, 1H), 7.70-7.56 (m,3H), 7.37 (d, J = 7.3 Hz, 1H), 7.13 (br d, J = 8.1 Hz, 1H), 6.79 (br s,1H), 6.12 (d, J = 16.1 Hz, 1H), 5.68 (dd, J = 16.0, 8.5 Hz, 1H), 4.12(br t, J = 7.8 Hz, 2H), 3.57 (br t, J = 6.5 Hz, 2H), 3.46-3.35 (m, 1H),2.23-2.13 (m, 1H), 1.13-1.02 (m, 4H). A2 173

MS (ESI) m/z: 537.3 [M + H]⁺; EC₅₀ = 375; ¹H NMR (500 MHz, Methanol-d₄)δ 8.28 (d, J = 9.4 Hz, 1H), 7.95-7.86 (m, 2H), 7.81-7.76 (m, 1H), 7.75-7.70 (m, 1H), 7.50 (d, J = 7.5 Hz, 1H), 7.14 (d, J = 9.7 Hz, 1H), 6.29(d, J = 16.1 Hz, 1H), 5.83 (dd, J = 15.8, 8.3 Hz, 1H), 4.55 (br t, J =9.0 Hz, 2H), 4.25 (s, 3H), 4.05 (br dd, J = 9.3, 6.2 Hz, 2H), 3.63-3.54(m, 1H), 2.35-2.28 (m, 1H), 1.25-1.16 (m, 4H). A2 174

MS (ESI) m/z: 579.2 [M + H]⁺; EC₅₀ = 324; ¹H NMR (500 MHz, Methanol-d₄)δ 8.84 (br d, J = 4.13 Hz, 1H), 8.13 (br d, J = 8.80 Hz, 1H), 7.99 (brd, J = 7.43 Hz, 1H), 7.79 (dd, J = 4.68, 7.70 Hz, 1H), 7.31 (br s, 1H),7.29 (s, 1H), 6.94 (d, J = 1.38 Hz, 1H), 6.27 (d, J = 15.96 Hz, 1H),5.78-5.89 (m, 2H), 5.20 (t, J = 6.74 Hz, 2H), 4.89 (br dd, J = 4.54,7.57 Hz, 2H), 4.29 (br t, J = 7.84 Hz, 2H), 3.77 (br d, J = 6.88 Hz,2H), 3.51-3.63 (m, 1H), 2.30 (br s, 1H), 1.18-1.22 (m, 2H), 1.16 (br d,J = 3.03 Hz, 2H). A2 175

MS (ESI) m/z: 564.3 [M + H]⁺; EC₅₀ = 1891; ¹H NMR (400 MHz, Methanol-d₄)δ 8.88-8.76 (m, 1H), 8.25 (d, J = 9.5 Hz, 1H), 8.02-7.93 (m, 1H), 7.87(s, 1H), 7.81 (dd, J = 7.9, 4.8 Hz, 1H), 7.30 d, J = 9.5 Hz, 1H), 6.13(d, J = 16.1 Hz, 1H), 5.27 (dd, J = 16.1, 8.8 Hz, 1H), 4.26 (s, 3H),4.11-3.85 (m, 2H), 3.72 (dt, J = 11.3, 2.0 Hz, 2H), 2.25 (tt, J = 8.2,5.2 Hz, 1H), 1.86-1.74 (m, 2H), 1.36 (dt, J = 8.8, 3.3 Hz, 1H),1.31-0.96 (m, 4H). A2 176

MS (ESI) m/z: 564.3 [M + H]⁺; EC₅₀ = 1347; ¹H NMR (400 MHz, DMSO-d₆) δ8.86 (s, 2H), 8.24 (dd, J = 2.2 Hz, 1H), 8.12 (dd, J = 8.8, 2.3 Hz, 1H),7.33 (d, J = 8.8 Hz, 1H), 6.15 (d, J = 16.1 Hz, 1H), 5.28 (dd, J = 16.1,8.8 Hz, 1H), 3.92 (s, 3H), 3.62 (d, J = 10.1 Hz, 2H), 3.45 (d, J = 9.9Hz, 2H), 2.43- 2.26 (m, 1H), 1.72 (s, 2H), 1.47-1.35 (m, 1H), 1.22-0.94(m, 4H). H 178

MS (ESI) m/z: 563.3 [M + H]⁺; EC₅₀ = 37; ¹H NMR (400 MHz, Methanol-d₄) δ8.84 (d, J = 3.74 Hz, 1H), 8.14 (br d, J = 8.80 Hz, 1H), 8.05 (s, 1H),7.96-8.02 (m, 1H), 7.80 (dd, J = 4.84, 7.92 Hz, 1H), 7.31 (br d, J =8.14 Hz, 1H), 6.80 (d, J = 2.20 Hz, 1H), 6.19-6.34 (m, 1H), 5.83 (dd, J= 8.14, 16.07 Hz, 1H), 4.41 (br s, 1H), 4.27 (br t, J = 8.03 Hz, 2H),3.74 (br s, 2H), 3.51-3.61 (m, 1H), 2.25-2.35 (m, 1H), 1.15-1.25 (m,4H), 1.08-1.14 (m, 2H), 1.04 (br s, 2H). A2 180

MS (ESI) m/z: 563.3 [M + H]⁺; EC₅₀ = 276; ¹H NMR (400 MHz, DMSO-d₆) δ8.87 (s, 2H), 8.83 (s, 1H), 8.10 (d, J = 9.0 Hz, 1H), 6.93 (dd, J = 9.2,2.1 Hz, 1H), 6.48 (d, J = 2.1 Hz, 1H), 6.15 (d, J = 16.1 Hz, 1H), 5.31(dd, J = 16.1, 8.9 Hz, 1H), 3.96 (s, 3H), 3.75 (d, J = 10.0 Hz, 2H),3.51-3.46 (m, 2H), 2.38 (ddd, J = 8.3, 6.9, 4.1 Hz, 1H), 1.90-1.79 (m,2H), 1.39 (dt, J = 9.0, 3.3 Hz, 1H), 1.26-0.99 (m, 4H). A2 181

MS (ESI) m/z: 536.2 [M + H]⁺; EC₅₀ = 400; ¹H NMR (400 MHz, DMSO-d₆) δ8.83 (s, 1H), 8.11 (d, J = 8.9 Hz, 1H), 7.94 (dd, J = 7.8, 1.4 Hz, 1H),7.87-7.71 (m, 2H), 7.55 (d, J = 7.4 Hz, 1H), 6.71 (dd, J = 9.0, 2.0 Hz,1H), 6.37 (d, J = 2.0 Hz, 1H), 6.23 (dd, J = 16.1, 1.0 Hz, 1H), 5.76(dd, J = 16.1, 8.9 Hz, 1H), 4.22 (t, J = 8.2 Hz, 2H), 3.94 (s, 3H), 3.71(dd, J = 8.2, 6.0 Hz, 2H), 3.52 (h, J = 7.5 Hz, 1H), 2.41 (tt, J = 8.3,5.1 Hz, 1H), 1.23-0.92 (m, 4H). A2 182

MS (ESI) m/z: 586.3 [M + H]⁺; EC₅₀ = 72; ¹H NMR (500 MHz, Methanol-d₄) δ8.18- 8.09 (m, 1H), 7.89 (d, J = 7.7 Hz, 1H), 7.81-7.68 (m, 3H), 7.49(br d, J = 7.4 Hz, 1H), 7.25 (br d, J = 8.3 Hz, 1H), 6.88 (br s, 1H),6.60-6.31 (m, 1H), 6.25 (br d, J = 16.0 Hz, 1H), 5.81 (br dd, J = 15.8,8.4 Hz, 1H), 4.81-4.72 (m, 2H), 4.26 (br t, J = 7.7 Hz, 2H), 3.70 (br t,J = 6.3 Hz, 2H), 3.58-3.49 (m, 1H), 2.34-2.26 (m, 1H), 1.24-1.15 (m,4H). A2 183

MS (ESI) m/z: 587.2 [M + H]⁺; EC₅₀ = 908; ¹H NMR (500 MHz, DMSO-d₆) δ8.00 (bs, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.87-7.62 (m, 4H), 7.48 (d, J =7.5 Hz, 1H), 7.34 (bs, 1H), 7.24 (dd, J = 9.3, 2.7 Hz, 1H), 6.75 (d, J =2.7 Hz, 1H), 6.04 (d, J = 16.1 Hz, 1H), 5.19 (dd, J = 16.1, 8.8 Hz, 1H),4.27-3.97 (m, 1H), 3.62 (d, J = 9.8 Hz, 2H), 3.41-3.27 (m, 2H), 2.26(td, J = 8.5, 4.3 Hz, 1H), 1.73-1.64 (m, 2H), 1.36-1.31 (m, 1H),1.15-1.11 (m, 2H), 1.07- 1.01 (m, 2H), 0.97-0.90 (m, 2H), 0.84-0.77 (m,2H). J1 184

MS (ESI) m/z: 588.3 [M + H]⁺; HLE GAL-FXR EC₅₀ = 50; ¹H NMR (400 MHz,Methanol-d₄) δ 8.16 (d, J = 9.1 Hz, 1H), 8.06 (s, 1H), 7.98-7.83 (m,1H), 7.83-7.66 (m, 2H), 7.58 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 7.2 Hz,1H), 7.03-6.80 (m, 1H), 6.11 (d, J = 16.1 Hz, 1H), 5.22 (dd, J = 16.0,8.7 Hz, 1H), 4.47-4.40 (m, 1H), 3.74 (d, J = 9.9 Hz, 2H), 3.52 (d, J =10.1 Hz, 2H), 2.24 (tt, J = 8.0, 5.2 Hz, 1H), 1.82-1.67 (m, 2H),1.49-1.25 (m, 1H), 1.28-0.79 (m, 8H). J2 185

MS (ESI) m/z: 620.3 [M + H]; EC₅₀ = 11; ¹H NMR (400 MHz, Methanol-d₄) δ8.15 (d, J = 9.4 Hz, 1H) ,7.90 (dd, J = 7.6, 1.6 Hz, 1H), 7.83-7.67 (m,2H), 7.56 (dd, J = 9.5, 2.6 Hz, 1H), 7.53 (s, 1H), 7.49- 7.43 (m, 1H),7.06 (d, J = 2.6 Hz, 1H), 6.12 (d, J = 16.1 Hz, 1H), 5.22 (dd, J = 1.61,8.8 Hz, 1H), 5.06 (p, J = 6.3 Hz, 1H), 5.00-4.89 (m, 2H), 3.77 (d, J =10.1 Hz, 2H), 3.66-3.48 (m, 2H), 3.31-3.22 (m, 2H), 2.72-2.52 (m, 1H),2.24 (tt, J = 8.2, 5.3 Hz, 1H), 1.82-1.72 (m, 2H), 1.38 (dt, J = 8.8,3.3 Hz, 1H), 1.29-0.97 (m, 4H). A2 186

MS (ESI) m/z: 550.2 [M + H]⁺; EC₅₀ = 228; ¹H NMR (500 MHz, Methanol-d₄)δ 8.22 (br s, 1H), 8.17-8.08 (m, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.81-7.75 (m, 1H), 7.75-7.69 (m, 1H), 7.49 (d, J = 7.4 Hz, 1H), 7.17 (br d, J= 8.5 Hz, 1H), 6.61 (br s, 1H), 6.25 (br d, J = 16.0 Hz, 1H), 5.82 (brdd, J = 15.7, 8.3 Hz, 1H), 4.93 (br s, 2H), 4.26 (br t, J = 7.4 Hz, 2H),3.75-3.66 (m, 2H), 3.57 (s, 3H), 3.55-3.50 (m, 1H), 2.34-2.27 (m, 1H),1.25-1.16 (m, 4H). A2 187

MS (ESI) m/z: 594.2 [M + H]+; EC₅₀ = 348; ¹H NMR (500 MHz, Methanol-d₄)δ 8.14 (br d, J = 9.4 Hz, 1H), 7.90 (d, J = 7.7 Hz, 1H), 7.82-7.75 (m,1H), 7.75-7.69 (m, 1H), 7.53 (s, 1H), 7.50 (d, J = 7.4 Hz, 1H), 7.29 (brd, J = 7.4 Hz, 1H), 6.92 (d, J = 1.7 Hz, 1H), 6.26 (d, J = 16.0 Hz, 1H),5.82 (dd, J = 16.1, 8.4 Hz, 1H), 5.08-4.90 (m, 2H), 4.28 (t, J = 7.8 Hz,2H), 3.73 (t, J = 6.7 Hz, 2H), 3.60-3.50 (m, 1H), 3.29 (td, J = 7.0, 3.9Hz, 2H), 2.68-2.55 (m, 2H), 2.35-2.26 (m, 1H), 1.24-1.16 (m, 4H). A2 188

MS (ESI) m/z: 593.3 [M + H]⁺; EC₅₀ = 1690; ¹H NMR (400 MHz, Methanol-d₄)δ 8.84 (d, J = 3.96 Hz, 1H), 8.13 (br d, J = 8.58 Hz, 1H), 7.98 (d, J =7.04 Hz, 1H), 7.79 (dd, J = 4.73, 7.81 Hz, 1H), 7.68 (s, 1H), 7.30 (brd, J = 8.36 Hz, 1H), 6.88 (s, 1H), 6.26 (d, J = 16.07 Hz, 1H), 5.85 (brd, J = 8.14 Hz, 1H), 5.61 (br s, 1H), 4.23-4.33 (m, 2H), 4.16- 4.23 (m,1H), 4.02-4.15 (m, 2H), 3.96 (br d, J = 4.84 Hz, 1H), 3.75 (br t, J =6.38 Hz, 2H), 3.56 (br d, J = 6.16 Hz, 1H), 2.47-2.61 (m, 1H), 2.24-2.36(m, 2H), 1.12-1.23 (m, 4H). A2 189

MS (ESI) m/z: 593.2 [M + H]⁺; EC₅₀ = 650; ¹H NMR (400 MHz, Methanol-d₄)δ 8.80-8.87 (m, 1H), 8.14 (br d, J = 9.24 Hz, 1H), 7.95-8.02 (m, 1H),7.80 (dd, J = 4.73, 8.03 Hz, 1H), 7.69 (s, 1H), 7.30 (dd, J = 2.0, 9.24Hz, 1H), 6.90 (d, J = 2.42 Hz, 1H), 6.27 (dd, J = 0.88, 16.07 Hz, 1H),5.84 (dd, J = 8.36, 16.07 Hz, 1H), 5.61 (br s, 1H), 4.28 (t, J = 8.03Hz, 2H), 4.18-4.23 (m, 1H), 4.05-4.16 (m, 2H), 3.96 (br d, J = 4.84 Hz,1H), 3.71-3.80 (m, 2H), 3.53-3.62 (m, 1H), 2.49-2.62 (m, 1H), 2.25-2.37(m, 2H), 1.15-1.24 (m, 4H). A2 190

MS (ESI) m/z: 562.3 [M + H]⁺; EC₅₀ = 376; ¹H NMR (400 MHz, DMSO-d₆) δ8.75 (s, 1H), 8.01 (d, J = 9.1 Hz, 1H), 7.86 (dd, J = 7.7, 1.5 Hz, 1H),7.80-7.66 (m, 2H), 7.48-7.41 (m, 1H), 6.84 (dd, J = 9.2, 2.0 Hz, 1H),6.39 (d, J = 2.1 Hz, 1H), 6.00 (d, J = 16.1 Hz, 1H), 5.12 (dd, J = 16.1,9.0 Hz, 1H), 3.88 (s, 3H), 3.65 (d, J = 10.5 Hz, 2H), 3.43-3.35 (m, 2H),2.25-2.15 (m, 1H), 1.73-1.60 (m, 2H), 1.29-1.14 (m, 1H), 1.12-1.03 (m,2H), 1.06-0.95 (m, 2H). A2 191

MS (ESI) m/z: 512.2 [M + H]⁺; EC₅₀ = 40; ¹H NMR (400 MHz, Methanol-d₄) δ8.16 (d, J = 9.4 Hz, 1H), 7.90 (dd, J = 7.7, 1.6 Hz, 1H), 7.84-7.69 (m,3h), 7.61-7.51 (m, 1H), 7.46 (dd, J = 7.5, 1.6 Hz, 1H), 7.04 (s, 1H),6.73-6.27 (m, 1H), 6.12 (d, J = 16.1 Hz, 1H), 5.22 (dd, J = 16.1, 8.7Hz, 1H), 4.81 (dd, J = 13.8, 3.4 Hz, 2H), 3.75 (d, J = 10.0 Hz, 2H),3.60-3.45 (m, 2H), 2.24 (tt, J = 8.2, 5.3 Hz, 1H), 1.72-1.82 (m, J = 3.1Hz, 2H), 1.37 (dt, J = 8.9, 3.3 Hz, 1H), 1.20-1.12 (m, 4H). A2 192

MS (ESI) m/z: 576.3 [M + H]⁺; EC₅₀ = 132.0; ¹H NMR (400 MHz, DMSO-d₆) δ8.82 (s, 1H), 8.10 (d, J = 9.1 Hz, 1H), 7.94 (dd, J = 7.8, 1.6 Hz, 1H),7.88-7.67 (m, 2H), 7.56-7.40 (m, 1H), 6.91 (dd, J = 9.1, 2.0 Hz, 1H),6.51 (d, J = 2.1 Hz, 1H), 6.07 (d,J = 16.1 Hz, 1H), 5.20 (dd, J = 16.1,8.9 Hz, 1H), 4.47 (q, J = 7.1 Hz, 2H), 3.72 (d, J = 10.4 Hz, 2H),3.50-3.42 (m, 2H), 2.36-2.27 (m, 1H), 1.81-1.68 (m, 2H), 1.39 (t, J =7.0 Hz, 3H), 1.38 (dt, J = 8.8, 3.3 Hz, 1H), 1.20-1.10 (m, 2H),1.11-0.94 (m, 2H). A2 193

MS (ESI) m/z: 592.3 [M + H]⁺; EC₅₀ = 343; ¹H NMR (500 MHz, Methanol-d₄)δ 8.15 (br d, J = 8.8 Hz, 1H), 7.89 (d, J = 7.7 Hz, 1H), 7.81-7.67 (m,3H), 7.49 (d, J = 7.7 Hz, 1H), 7.30 (br d, J = 8.5 Hz, 1H), 6.90 (s,1H), 6.25 (d, J = 16.0 Hz, 1H), 5.81 (dd, J = 16.1, 8.4 Hz, 1H), 5.61(br s, 1H), 4.32-4.19 (m, 3H), 4.18-4.06 (m, 2H), 3.98 (td, J = 8.4, 5.0Hz, 1H), 3.72 (br t, J = 6.5 Hz, 2H), 3.59-3.50 (m, 1H), 2.62-2.51 (m,1H), 2.38-2.26 (m, 2H), 1.24-1.16 (m, 4H). A2 194

MS (ESI) m/z: 594.2 [M + H]⁺; EC₅₀ = 159; ¹H NMR (400 MHz, Methanol-d₄)δ 8.01 (br d, J = 9.2 Hz, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.71-7.56 (m,2H), 7.42-7.32 (m, 2H), 7.16 (br d, J = 8.1 Hz, 1H), 6.78 (d, J = 1.1Hz, 1H), 6.14 (d, J = 16.1 Hz, 1H), 5.69 (dd, J = 16.1, 8.4 Hz, 1H),5.36 (td, J = 6.7, 3.3 Hz, 2H), 4.15 (br t, J = 7.8 Hz, 2H), 3.60 (br t,J = 6.6 Hz, 2H), 2.93-2.62 (m, 4H), 2.25-2.12 (m, 1H), 1.15-1.01 (m,5H). A2 195

MS (ESI) m/z: 595.3 [M + H]⁺; EC₅₀ = 286; ¹H NMR (500 MHz, Methanol-d₄)δ 8.80-8.87 (m, 1H), 8.13 (br d, J = 7.98 Hz, 1H), 7.98 (d, J = 7.43 Hz,1H), 7.79 (dd, J = 4.68, 7.70 Hz, 1H), 7.52 (s, 1H), 7.31 (br d, J =7.43 Hz, 1H), 6.91 (br s, 1H), 6.26 (d, J = 15.96 Hz, 1H), 5.84 (dd, J =8.25, 15.96 Hz, 1H), 5.03 (quin, J = 6.33 Hz, 1H), 4.87-4.96 (m, 2H),4.29 (br t, J = 7.43 Hz, 2H), 3.76 (br s, 2H), 3.56 (br d, J = 7.15 Hz,1H), 3.21-3.26 (m, 1H), 2.52-2.66 (m, 2H), 2.26-2.34 (m, 1H), 1.18-1.23(m, 2H), 1.16 (br d, J = 3.03 Hz, 2H). A2 196

MS (ESI) m/z: 562.2 [M + H]⁺; EC₅₀ = 53; ¹H NMR (400 MHz, Methanol-d₄) δ8.01 (br d, J = 9.2 Hz, 1H), 7.93 (s, 1H), 7.77 (d, J = 7.5 Hz, 1H),7.70-7.55 (m, 2H), 7.37 (d, J = 7.3 Hz, 1H), 7.15 (dd, J = 8.5, 1.4 Hz,1H), 6.69 (d, J = 2.0 Hz, 1H), 6.12 (d, J = 16.1 Hz, 1H), 5.68 (dd, J =15.8, 8.4 Hz, 1H), 4.30-4.22 (m, 1H), 4.13 (t, J = 7.8 Hz, 2H), 3.57(t,J = 6.7 Hz, 2H), 3.45-3.36 (m, 1H), 2.23-2.13 (m, 1H), 1.12-1.04 (m,4H), 1.02-0.96 (m, 2H), 0.95-0.88 (m, 2H). A2 197

MS (ESI) m/z: 602.3 [M + H]⁺; EC₅₀ = 373; ¹H NMR (400 MHz, DMSO-d₆) δ8.85 (s, 1H), 8.11 (d, J = 9.1 Hz, 1H), 7.93 (dd, J = 7.7, 1.5 Hz, 1H),7.88-7.70 (m, 2H), 7.59-7.42 (m, 1H), 6.92 (dd, J = 9.2, 2.0 Hz, 1H),6.62 (d, J = 2.1 Hz, 1H), 6.07 (d, J = 16.1 Hz, 1H), 5.20 (dd, J = 16.1,8.9 Hz, 1H), 4.32 (d, J = 7.2 Hz, 2H), 3.73 (d, J = 10.3 Hz, 2H),3.54-3.38 (m, 2H), 2.38-2.18 (m, 1H), 1.81-1.72 (m, 2H), 1.55-1.37 (m,1H), 1.34 (dt, J = 9.0, 3.2 Hz, 1H), 1.22-1.10 (m, 2H), 1.11-0.98 (m,2H), 0.66-0.51 (m, 2H), 0.51-0.41 (m, 2H). A2 198

MS (ESI) m/z: 581.2 [M + H]⁺; EC₅₀ = 71; ¹H NMR (400 MHz, Methanol-d₄) δ8.74 (s, 2H), 7.59 (s, 1H), 7.24-6.94 (m, 1H), 6.81 (s, 1H), 6.17 (d, J= 16.0 Hz, 1H), 5.29 (dd, J = 16.0, 8.8 Hz, 1H), 4.17 (s, 3H), 3.71 (d,J = 9.8 Hz, 2H), 3.61-3.39 (m, 2H), 2.33-2.24 (m, 1H), 1.79 (d, J = 3.3Hz, 2H), 1.50-1.39 (m, 1H), 1.26-1.09 (m, 4H). A2 199

MS (ESI) m/z: 620.3 [M + H]⁺; EC₅₀ = 63; ¹H NMR (400 MHz, Methanol-d₄) δ8.15 (d, J = 9.4 Hz, 1H), 7.90 (dd, J = 7.6, 1.6 Hz, 1H), 7.84-7.62 (m,2H), 7.56 (dd, J = 9.5, 2.7 Hz, 1H), 7.50 (s, 1H), 7.47 (dd, J = 7.5,1.6 Hz, 1H), 7.04 (d, J = 2.6 Hz, 1H), 6.11 (d, J = 16.0 Hz, 1H),5.62-5.29 (m, 3H), 5.22 (dd, J = 16.1, 8.7 Hz, 1H), 3.77 (d, J = 10.1Hz, 2H), 3.58-3.38 (m, 2H), 3.07-2.90 (m, 2H), 2.90- 2.76 (m, 2H),2.31-2.16 (m, 1H), 1.83-1.71 (m, 2H), 1.37 (dt, J = 8.7, 3.3 Hz, 1H),1.25-1.08 (m, 4H). A2 200

MS (ESI) m/z: 613.2 [M + H]⁺; EC₅₀ = 21; ¹H NMR (400 MHz, Methanol-d₄) δ8.74 (s, 2H), 8.18 (d, J = 9.4 Hz, 1H), 7.79 (s, 1H), 7.59 (d, J = 9.3Hz, 1H), 7.06 (d, J = 2.4 Hz, 1H), 6.77-6.28 (m, 1H), 6.17 (d, J = 16.1Hz, 1H), 5.30 (dd, J = 16.0, 8.7 Hz, 1H), 4.90-4.90 (m, 2H), 3.78 (d, J= 10.1 Hz, 2H), 3.55 (d, J = 10.2 Hz, 2H), 2.29 (tt, J = 8.1, 5.3 Hz,1H), 1.91-1.77 (m, 2H), 1.52-1.33 (m, 1H), 1.30-1.00 (m, 4H). A2 201

MS (ESI) m/z: 508.2 [M + H]⁺; EC₅₀ = 178; ¹H NMR (500 MHz, Methanol-d₄)δ 7.95 (d, J = 8.5 Hz, 1H), 7.90 (d, J = 7.4 Hz, 1H), 7.83-7.70 (m, 3H),7.49 (d, J = 7.4 Hz, 1H), 6.68-6.60 (m, 2H), 6.23 (d, J = 16.5 Hz, 1H),5.80 (dd, J = 16.1, 8.4 Hz, 1H), 4.19 (br t, J = 7.6 Hz, 2H), 3.81 (s,3H), 3.69-3.63 (m, 2H), 3.52-3.45 (m, 1H), 2.34-2.27 (m, 1H), 1.24-1.15(m, 4H). A2 202

MS (ESI) m/z: 566.2 [M + H]⁺; EC₅₀ = 30; ¹H NMR (400 MHz, Methanol-d₄) δ8.74 (s, 2H), 8.16 (d, J = 9.5 Hz, 1H), 7.74 (s, 1H), 7.56 (dd, J = 9.5,2.6 Hz, 1H), 7.07 (d, J = 2.6 Hz, 1H), 6.17 (d, J = 16.0 Hz, 1H), 5.30(dd, J = 16.0, 8.7 Hz, 1H), 3.78 (d, J = 10.0 Hz, 2H), 3.53 (d, J = 9.8Hz, 2H), 2.35-2.23 (m, 1H), 1.88-1.79 (m, 2H), 1.44 (dt, J = 8.1, 4.2Hz, 1H), 1.28-0.96 (m, 4H). A2 203

MS (ESI) m/z: 621.2 [M + H]⁺; EC₅₀ = 16; ¹H NMR (400 MHz, Methanol-d₄) δ8.63 (s, 2H), 8.04 (d, J = 9.3 Hz, 1H), 7.45 (dd, J = 8.5, 2.6 Hz, 1H),7.42 (s, 1H), 6.96 (d, J = 2.8 Hz, 1H), 6.06 (d, J = 16.0 Hz, 1H), 5.19(dd, J = 16.1, 8.7 Hz, 1H), 5.04-4.78 (m, 2H), 3.68 (d, J = 10.0 Hz,2H), 3.51-3.30 (m, 2H), 3.08-3.31 (m, 2H), 2.62-2.33 (m, 2H), 2.17 (tt,J = 8.2, 5.2 Hz, 1H), 1.76-1.69 (m, 2H), 1.33 (dt, J = 8.7, 3.2 Hz, 1H),1.28-0.96 (m, 4H). A2 204

MS (ESI) m/z: 621.3 [M + H]⁺; EC₅₀ = 19; ¹H NMR (500 MHz, Methanol-d₄) δ8.74 (s, 2H), 8.17 (d, J = 9.4 Hz, 1H), 7.59 (dd, J = 9.4, 2.6 Hz, 1H),7.52( s, 1H), 7.07 (d, J = 2.7 Hz, 1H), 6.17 (d, J = 16.1 Hz, 1H),5.60-5.35 (m, 2H), 5.31 (dd, J = 16.0, 8.7 Hz, 1H), 3.80 (d, J = 10.1Hz, 2H), 3.56 (d, J = 10.1, 2H), 3.05-2.91 (m, 2H), 2.92-2.76 (m, 2H),2.29 (tt, J = 8.2, 5.2 Hz, 1H), 1.89-1.78 (m, 2H), 1.52-1.37 (m, 1H),1.31-0.99 (m, 4H). A2 205

MS (ESI) m/z: 531.2 [M + H]⁺; EC₅₀ = 189; ¹H NMR (500 MHz, DMSO-d₆) δ7.97-7.93 (m, 3H), 7.86-7.81 (m, 1H), 7.80-7.75 (m, 1H), 7.70 (d, J =8.5 Hz, 2H), 7.61-7.52 (m, 3H), 6.49 (d, J = 8.5 Hz, 2H), 6.19 (d, J =16.0 Hz, 1H), 5.72 (dd, J = 16.1, 7.8 Hz, 1H), 4.05-4.00 (m, 2H),3.50-3.41 (m, 3H), 2.43-2.36 (m, 1H), 1.20-1.14 (m, 2H), 1.11-1.06(m,2H). A2 206

MS (ESI) m/z: 552.2 [M + H]⁺; EC₅₀ = 216; ¹H NMR (400 MHz, Methanol-d₄)δ 8.09-8.17 (m, 1H), 7.73 (s, 1H), 7.59-7.66 (m, 1H), 7.45-7.56 (m, 3H),7.31 (br dd, J = 1.87, 9.13 Hz, 1H), 6.90 (d, J = 2.20 Hz, 1H), 6.27 (d,J = 16.07 Hz, 1H), 6.00 (dd, J = 8.36, 16.07 Hz, 1H), 4.33 (s, 3H),4.27-4.31 (m, 2H), 3.78 (br t, J = 6.82 Hz, 2H), 3.54-3.64 (m, 1H),2.24-2.33 (m, 1H), 1.11-1.22 (m, 4H). A2 207

MS (ESI) m/z: 531.2 [M + H]⁺; EC₅₀ = 64; ¹H NMR (500 MHz, DMSO-d₆) δ8.09 (t, J = 1.7 Hz, 1H), 7.95 (d, J = 7.4 Hz, 1H), 7.87-7.74 (m, 4H),7.57- 7.49 (m, 4H), 6.49 (d, J = 8.8 Hz, 2H), 6.19 (d, J = 16.0 Hz, 1H),5.72 (dd, J = 16.0, 7.7 Hz, 1H), 4.06-3.98 (m, 2H), 3.49-3.41 (m, 3H),2.44-2.35 (m, 1H), 1.21-1.14 (m, 2H), 1.12-1.05 (m, 2H). A2 208

MS (ESI) m/z: 595.1 [M + H]⁺; EC₅₀ = 247; ¹H NMR (400 MHz, Methanol-d₄)δ 8.73 (s, 2H), 7.98 (t, J = 1.5 Hz, 1H), 7.60 (dd, J = 2.6, 1.4 Hz,1H), 7.53 (dd, J = 2.5, 1.6 Hz, 1H), 7.10 (s, 1H), 6.19 (d, J = 16.0 Hz,1H), 5.30 (dd, J = 16.0, 8.5 Hz, 1H), 3.91 (s, 3H), 3.80 (d, J = 10.5Hz, 2H), 3.78-3.72 (m, 2H), 2.28 (tt, J = 8.2, 5.3 Hz, 1H), 1.90-1.81(m, 2H), 1.47 (dt, J = 8.6, 3.5 Hz, 1H), 1.29-0.93 (m, 4H). K 209

MS (ESI) m/z: 536.1 [M + H]⁺; EC₅₀ = 472; ¹H NMR (400 MHz, Methanol-d₄)δ 8.62 (s, 2H), 8.16 (br s, 1H), 7.85-7.70 (m, 1H), 7.68-7.52 (m, 1H),6.04 (d, J = 16.1 Hz, 1H), 5.20 (br dd, J = 15.8, 8.4 Hz, 1H), 3.85 (brs, 3H), 3.63 (br d, J = 7.7 Hz, 2H), 3.43-3.31 (m, 2H), 2.23-2.11 (m,1H), 1.73 (br s, 2H), 1.42-1.31 (m, 1H), 1.12-1.05 (m, 4H). A2 210

MS (ESI) m/z: 596.1 [M + H]⁺; EC₅₀ = 670; ¹H NMR (400 MHz, Methanol-d₄)δ 8.74 (s, 2H), 8.10 (t, J = 1.5 Hz, 1H), 7.73 (dd, J = 2.6, 1.4 Hz,1H), 7.68 (dd, J = 2.6, 1.5 Hz, 1H), 6.16 (d, J = 16.1 Hz, 1H), 5.27(dd, J = 16.0, 8.7 Hz, 1H), 3.97 (d, J = 10.6 Hz, 2H), 3.94 (s, 3H),3.66 (dt, J = 10.6, 2.0 Hz, 2H), 2.28 (tt, J = 8.2, 5.2 Hz, 1H),1.76-1.60 (m, 2H), 1.50-1.36 (m, 1H), 1.27-1.09 (m, 4H). L 211

MS (ESI) m/z: 535.3 [M + H]⁺; EC₅₀ = 154; ¹H NMR (500 MHz, Methanol-d₄)δ 8.29 (s, 1H), 7.90 (d, J = 7.4 Hz, 1H), 7.86 (br s, 1H), 7.81-7.71 (m,3H), 7.47 (d, J = 7.2 Hz, 1H), 6.11 (d, J = 16.0 Hz, 1H), 5.24 (dd, J =15.8, 8.7 Hz, 1H), 3.97 (s, 3H),3 .73 (br d, J = 9.4 Hz, 2H), 3.49-3.42(m, 2H), 2.28- 2.20 (m, 1H), 1.79 (br s, 2H), 1.46-1.40 (m, 1H),1.22-1.13 (m, 4H). A2 212

MS (ESI) m/z: 575.2 [M + H]⁺; EC₅₀ = 21; ¹H NMR (500 MHz, Methanol-d₄) δ7.92 (br d, J = 9.1 Hz, 1H), 7.59-7.56 (m, 2H), 7.55-7.51 (m, 1H), 6.88(br d, J = 8.0 Hz, 1H), 6.50 (d, J = 1.4 Hz, 1H), 6.16 (d, J = 16.0 Hz,1H), 5.19 (dd, J = 16.0, 8.8 Hz, 1H), 4.69 (d, J = 7.4 Hz, 2H), 3.68 (d,J = 9.4 Hz, 2H), 3.32-3.30 (m, 2H), 2.31-2.23 (m, 1H), 1.65 (br s, 2H),1.51-1.44 (m, 2H), 1.23-1.15 (m, 4H), 0.56- 0.48 (m, 4H). A2 213

MS (ESI) m/z: 575.2; [M + H]⁺; EC₅₀ = 18; ¹H NMR (500 MHz, DMSO-d₆) δ7.79 (d, J = 8.8 Hz, 1H), 7.69-7.66 (m, 2H), 7.64-7.58 (m, 1H), 6.72(dd, J = 8.9, 1.8 Hz, 1H), 6.56 (s, 1H), 6.16 (d, J = 16.0 Hz, 1H), 5.15(dd, J = 16.0, 9.1 Hz, 1H), 4.24 (d, J = 6.9 Hz, 2H), 3.64 (d, J = 9.6Hz, 2H), 3.30-3.26 (m, 2H), 2.39-2.34 (m, 1H), 1.69 (br s, 2H), 1.43(dt, J = 8.8, 3.0 Hz, 1H), 1.33-1.26 (m, 1H), 1.20- 1.15 (m, 2H),1.12-1.07 (m, 2H), 0.52-0.47 (m, 2H), 0.43-0.38 (m, 2H). A2 214

MS (ESI) m/z: 596.1 [M + H]⁺; EC₅₀ = 107; ¹H NMR (400 MHz, DMSO-d₆) δ8.86 (s, 2H), 8.25 (t, J = 1.5 Hz, 1H), 7.81 (dd, J = 2.6, 1.4 Hz, 1H),7.52 (dd, J = 2.6, 1.5 Hz, 1H), 6.15 (d, J = 16.0 Hz, 1H), 5.33 (dd, J =16.1, 8.8 Hz, 1H), 3.87 (s, 3H), 3.81-3.51 (m, 4H), 2.46-2.28 (m, 1H),1.87-1.77 (m, 2H), 1.44 (dt, J = 8.9, 3.4 Hz, 1H), 1.23-1.02 (m, 4H). M215

MS (ESI) m/z: 554.2 [M + H]⁺; EC₅₀ = 199; ¹H NMR (500 MHz, Methanol-d₄)δ 7.90 (d, J = 7.7 Hz, 1H), 7.81-7.75 (m, 1H), 7.75-7.70 (m, 1H), 7.60(s, 1H), 7.49 (d, J = 7.4 Hz, 1H), 6.87 (br d, J = 11.6 Hz, 1H), 6.66(br s, 1H), 6.23 (d, J = 16.2 Hz, 1H), 5.80 (dd, J = 16.1, 8.4 Hz, 1H),4.20 (t, J = 7.8 Hz, 2H), 4.16 (s, 3H), 3.65 (t, J = 6.6 Hz, 2H),3.53-3.46 (m, 1H), 2.34-2.27 (m, 1H), 1.21 (dt, J = 8.3, 2.8 Hz, 2H),1.19-1.16 (m, 2H). A2 216

MS (ESI) m/z: 595.1 [M + H]⁺; EC₅₀ = 202; ¹H NMR (400 MHz, Methanol-d₄)δ 8.62 (s, 2H), 7.65 (s, 1H), 7.60 (t, J = 1.5 Hz, 1H), 7.45-7.41 (m,1H), 7.20 (t, J = 2.1 Hz, 1H), 6.08 (d, J = 16.0 Hz, 1H), 5.20 (dd, J =16.0, 8.5 Hz, 1H), 3.79 (s, 3H), 3.69 (d, J = 11.5 Hz, 2H), 3.65 (d, J =10.5 Hz, 2H), 2.16 (tt, J = 8.2, 5.3 Hz, 1H), 1.82-1.76 (m, 2H), 1.38(dt, J = 8.8, 3.5 Hz, 1H), 1.17-0.87 (m, 4H). A2 217

MS (ESI) m/z: 606.0 [M + H]⁺; EC₅₀ = 1400; ¹H NMR (500 MHz, Methanol-d₄)δ 8.13 (d, J = 9.08 Hz, 1H), 8.04 (s, 1H), 7.70 (s, 1H), 7.64 (s, 1H),7.50-7.59 (m, 2H), 7.27 (dd, J = 2.20, 8.80 Hz, 1H), 6.78-6.85 (m, 1H),6.40 (br d, J = 16.23 Hz, 1H), 5.90-6.05 (m, 1H), 4.38 (br d, J = 3.30Hz, 1H), 4.23-4.29 (m, 2H), 3.66-3.73 (m, 2H), 3.57-3.63 (m, 1H),1.06-1.13 (m, 2H), 1.03 (br s, 2H). A2 218

MS (ESI) m/z: 550.0 [M + H]⁺; EC₅₀ = 1600; ¹H NMR (400 MHz, Methanol-d₄)δ 8.67 (s, 2H), 8.48-8.51 (m, 1H), 8.14 (td, J = 1.35, 7.87 Hz, 1H),8.07-8.11 (m, 1H), 7.60 (t, J = 7.81 Hz, 1H), 6.10 (d, J = 15.85 Hz,1H), 5.29 (dd, J = 8.47, 15.96 Hz, 1H), 3.84 (d, J = 10.12 Hz, 2H), 3.71(br d, J = 10.56 Hz, 2H), 2.17-2.25 (m, 1H), 1.77 (br s, 2H), 1.44 (td,J = 3.22, 8.53 Hz, 1H), 1.20 (s, 2H), 1.18 (s, 2H). A2 219

MS (ESI) m/z: 562.0 [M + H]⁺; EC₅₀ = 117; ¹H NMR (500 MHz, Methanol-d₄)δ 8.72 (s, 2H), 7.79 (s, 1H), 7.47-7.54 (m, 2H), 7.44 (s, 1H), 7.30 (s,1H), 6.57 (br d, J = 8.53 Hz, 2H), 6.26 (d, J = 15.96 Hz, 1H), 5.84 (dd,J = 8.25, 15.96 Hz, 1H), 4.09 (br t, J = 7.43 Hz, 2H), 3.88 (s, 3H),3.56 (br t, J = 6.46 Hz, 2H), 3.46 (br d, J = 7.98 Hz, 1H), 2.28-2.36(m, 1H), 1.15-1.25 (m, 4H). A2 220

MS (ESI) m/z: 522.0 [M + H]⁺; EC₅₀ = 107; ¹H NMR (500 MHz, Methanol-d₄)δ 8.72 (s, 2H), 8.50( s, 1H), 8.01 (s, 1H), 7.55 (d, J = 8.80 Hz, 2H),6.55 (d, J = 8.80 Hz, 2H), 6.21-6.31 (m, 1H), 5.84 (dd, J = 8.25, 15.96Hz, 1H), 4.09 (t, J = 7.43 Hz, 2H), 3.55 (t, J = 6.46 Hz, 2H), 3.42-3.50(m, 1H), 2.27-2.37 (m, 1H), 1.17-1.24 (m, 4H). A2 221

MS (ESI) m/z: 562.1 [M + H]⁺; EC₅₀ 56; ¹H NMR (500 MHz, DMSO-d₆) δ 8.13(t, J = 1.4 Hz, 1H), 7.95 (d, J = 7.4 Hz, 1H), 7.88 (d, J = 2.5 Hz, 1H),7.86-7.81 (m, 2H), 7.80-7.76 (m, 1H), 7.75-7.72 (m, 1H), 7.55 (d, J =7.4 Hz, 1H), 7.39 (dd, J = 2.5, 1.4 Hz, 1H), 6.89 (dd, J = 8.7, 2.9 Hz,1H), 6.20 (d, J = 16.0 Hz, 1H), 5.75 (dd, J = 16.0, 8.3 Hz, 1H), 4.10(t, J = 7.6 Hz, 2H), 3.87 (s, 3H), 3.59-3.45 (m, 3H), 2.44-2.36 (m, 1H),1.20-1.15 (m, 2H), 1.12- 1.07 (m, 2H). 222

MS (ESI) m/z: 562.2 [M + H]⁺; EC₅₀ 34; ¹H NMR (500 MHz, DMSO-d₆) δ 8.39(d, J = 2.2 Hz, 1H), 8.00 (br d, J = 8.0 Hz, 1H), 7.95 (d, J = 7.7 Hz,1H), 7.87-7.81 (m, 1H), 7.81-7.76 (m, 1H), 7.71 (t, J = 1.5 Hz, 1H),7.55 (d, J = 7.4 Hz, 1H), 7.40 (s, 2H), 6.57 (br d, J = 8.8 Hz, 1H),6.20 (dd, J = 16.0, 0.8 Hz, 1H), 5.77 (dd, J = 16.1, 8.4 Hz, 1H), 4.21(t, J = 8.3 Hz, 2H), 3.87 (s, 3H), 3.74-3.70 (m, 2H), 3.47-3.40 (m, 1H),2.45-2.36 (m, 1H), 1.21-1.15 (m, 2H), 1.12-1.07 (m, 2H). 223

MS (ESI) m/z: 596.0 [M + H]⁺; EC₅₀ = 1400; ¹H NMR (500 MHz, Methanol-d₄)δ 8.70-8.75 (m, 2H), 7.94 (t, J = 1.38 Hz, 1H), 7.61 (dd, J = 1.38, 2.48Hz, 1H), 7.59 (d, J = 1.38 Hz, 1H), 6.18 (d, J = 15.96 Hz, 1H), 5.27(dd, J = 8.67, 16.09 Hz, 1H), 3.90 (s, 3H), 3.68-3.73 (m, 4H), 2.23-2.30(m, 1H), 1.79 (br s, 2H), 1.42-1.47 (m, 1H), 1.20 (td, J = 2.68, 8.39Hz, 2H), 1.16 (td, J = 2.68, 5.09 Hz, 2H). A2 224

MS (ESI) m/z: 601.0 [M + H]⁺; EC₅₀ = 166; ¹H NMR (400 MHz, Methanol-d₄)8.73 (s, 2H), 8.46 (s, 1H), 8.26-8.31 (m, 2H), 8.21 (dd, J = 2.31, 9.13Hz, 1H), 8.13 (s, 1H), 6.81-6.87 (m, 1H), 6.35 (dd, J = 0.88, 16.07 Hz,1H), 5.89 (dd, J = 8.47, 15.96 Hz, 1H), 4.46 (t, J = 8.80 Hz, 2H), 3.99(dd, J = 6.16, 9.02 Hz, 2H), 3.61-3.72 (m, 1H), 2.34 (ddd, J = 2.86,5.39, 8.25 Hz, 1H), 1.18-1.26 (m, 4H). A2 225

MS (ESI) m/z: 600.0 [M + H]⁺; EC₅₀ = 6; ¹H NMR (500 MHz, Methanol-d₄) δ8.44-8.48 (m, 1H), 8.25-8.30 (m, 2H), 8.20-8.25 (m, 1H), 8.14 (s, 1H),7.89 (d, J = 7.70 Hz, 1H), 7.70-7.80 (m, 2H), 7.48 (d, J = 7.43 Hz, 1H),6.84 (d, J = 9.08 Hz, 1H), 6.24-6.30 (m, 1H), 5.83 (dd, J = 8.53, 15.96Hz, 1H), 4.45 (t, J = 8.80 Hz, 2H), 3.95 (dd, J = 6.19, 8.94 Hz, 2H),3.62 (br d, J = 7.98 Hz, 1H), 2.26-2.35 (m, 1H), 1.13-1.25 (m, 4H). A2226

MS (ESI) m/z: 550.1 [M + H]⁺; EC₅₀ = 14; ¹H NMR (400 MHz, Methanol-d₄) δ8.19-8.26 (m, 2H), 8.07 (t, J = 1.43 Hz, 1H), 7.90 (d, J = 7.48 Hz, 1H),7.70-7.80 (m, 3H), 7.66 (dd, J = 1.76, 9.68 Hz, 1H), 7.46-7.51 (m, 1H),6.85-6.90 (m, 1H), 6.28 (dd, J = 0.88, 16.07 Hz, 1H), 5.84 (dd, J =8.36, 16.07 Hz, 1H), 4.47 (t, J = 8.91 Hz, 2H), 3.99 (dd, J = 6.16, 9.24Hz, 2H), 3.58-3.6 (m, 1H), 2.31 (s, 1H), 1.16-1.23 (m, 4H). A2 227

MS (ESI) m/z: 600.1 [M + H]⁺; EC₅₀ = 4; ¹H NMR( 400 MHz, Methanol-d₄) δ8.69 (s, 1H), 8.37 (s, 1H), 8.31 (s, 1H), 7.96 (d, J = 8.80 Hz, 1H),7.88 (d, J = 7.48 Hz, 1H), 7.83-7.86 (m, 1H), 7.68-7.80 (m, 2H), 7.47(d, J = 7.26 Hz, 1H), 7.24 (dd, J = 2.86, 8.80 Hz, 1H), 6.23 (d, J =16.07 Hz, 1H), 5.81 (d, J = 8.36 Hz, 1H), 4.23 (t, J = 7.92 Hz, 2H),3.67-3.74 (m, 2H), 3.49-3.60 (m, 1H), 2.24-2.33 (m, 1H), 1.18 (tdd, J =2.45, 8.31, 11.22 Hz, 4H). A2

Biological Evaluation

The exemplified compounds of the present invention were tested in thetransient human FXR/Gal4-luciferase reporter assay, and assay resultswere described in Table 1.

A Gal4-hFXR fusion construct reporter system was used as the primaryassay to characterize compound activity. A construct including 5 copiesof the Gal4 promoter response element upstream of a firefly luciferasereporter cDNA was stably expressed in HEK293 cells. This reporter cellline was maintained in Dulbecco's Modified Eagle's medium (DMEM; Gibco)supplemented with 1% penicillin-streptomycin (P/S) solution, 500 μg/mLZeocin and 10% charcoal/dextran-treated fetal bovine serum (cs-FBS) at37° C. in a humidified 5% CO₂ atmosphere. Another plasmid wasconstructed in which the human cytomegalovirus promoter in the pcDNA3.1vector directs the expression of the cDNA encoding a fusion proteincomprised of the DNA binding domain from the Gal4 transcription factorfused to the ligand binding domain from human FXR.

The day prior to transfection, the reporter cells in culture aredetached from the plate with trypsin and plated into a T75 flask at asufficient density to achieve approximately 90% confluence the nextmorning. The transfection reagents are prepared by separately diluting25 μg of the pcDNA3.1-Gal4-FXR plasmid into 1.87 mL of Opti-MEM(Thermo-Fisher), and 40 μL of Lipofectamine 2000 (Thermo-Fisher) into1.87 mL of Opti-MEM, and then adding the diluted DNA solution into thediluted Lipofectamine 2000 solution and incubating at room temperaturefor 15-20 minutes. The mixture is further diluted with 10 mL of asolution comprised of DMEM, 10% cs-FBS, and 1% P/S immediately prior totransferring to the cells. The maintenance culture media is aspiratedfrom the cells and the final transfection mixture is added before thecells are incubated overnight at 37° C. in a humidified 5% CO₂atmosphere. This protocol can be scaled up, and the transientlytransfected cells can be cryopreserved in an assay-ready format.

For compound testing, 100 nL of the compounds (serial dilutions in DMSO)are dispensed with an Echo acoustic dispenser (Labcyte) into the wellsof a Corning/Costar clear bottom 384-well white plate. The transfectedcells are harvested, counted, and diluted such that 10-25,000 cells in25 μL are plated into each well of the 384-well compound assay plate.The compound-treated cells are incubated overnight at 37° C. in ahumidified 5% CO₂ atmosphere. The next morning 25 μL of Steady-Glo(Promega) are added to each well of the plate, the mixture is incubatedfor 15 min. with shaking, and luminescence is measured on an Envision(Perkin Elmer) plate reader. Background counts from cells treated withDMSO alone are subtracted from all raw counts, and the corrected valuesare converted to a percentage of the control response attained with 8 μMGW-4064. These data are fit to a 4-parameter log agonist-responseequation to calculate an EC₅₀ value.

Acute Mouse In Vivo Assay:

Male, C57BL6/NTac mice, weighing 25-28 g, are purchased from TaconicLabs (Hudson, N.Y.) and maintained on Teklad Global 18% Protein RodentDiet (Harlan Laboratories). After 1 week acclimation, mice are sortedinto groups based upon body weight. Mice are administered a single oraldose of vehicle or experimental compound. Systemic compound exposure isevaluated in plasma derived from blood collected via the submandibularvein at 1 hour post-dose, and at study termination (6 h). At studytermination, the animals are euthanized and rapidly dissected. Themedial lobe of the liver is divided, with one half being homogenized andanalyzed for compound exposure, and the other half saved in RNAlater(Thermo-Fisher Scientific). The ileum is also dissected and preserved inRNAlater. Tissue samples in RNAlater are homogenized with MPBiomedicals' beads. RNA is extracted using the MagMax-96 Total RNAIsolation kit (Thermo-Fisher Scientific) according to the manufacturer'sprotocol. RNA Concentration is determined with the Nano-Drop 8000Spectrophotometer (Thermo Fisher). Reverse transcription is done withInvitrogen's SuperScript® VILO cDNA Synthesis Kit according to themanufacturer's protocol. Real time PCR is done with Applied Biosystems'Taqman PCR master mixture according to the manufacturer's protocol. Allprimers are purchased from Thermo-Fisher Scientific. Mouse genesanalyzed include Nr0b2 (which encodes the small heterodimer partner,SHP), Abcb11 (which encodes the bile salt excretion pump, BSEP), Cyp7a1,& Cyp8b1 in liver, and Fgf15, Fabp6 (which encodes ileal bile acidbinding protein, I-BABP), Slc51a (which encodes organic solutetransporter alpha subunit, OSTA), and Slc51 b (which encodes organicsolute transporter beta subunit, OSTB) in the ileum. The statisticalsignificant changes in FGF15 gene expression are expressed as foldincrease and CYP_(7A1) expression as a percent reduction relative tovehicle control.

Other features of the invention should become apparent in the course ofthe above descriptions of exemplary embodiments that are given forillustration of the invention and are not intended to be limitingthereof. The present invention may be embodied in other specific formswithout departing from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of preferred aspects of theinvention noted herein. It is understood that any and all embodiments ofthe present invention may be taken in conjunction with any otherembodiment or embodiments to describe additional embodiments. It is alsounderstood that each individual element of the embodiments is its ownindependent embodiment. Furthermore, any element of an embodiment ismeant to be combined with any and all other elements from any embodimentto describe an additional embodiment.

Biological Evaluation

The exemplified compounds of the present invention were tested in thetransient human FXR/Gal4-luciferase reporter assay, and assay resultswere described in the EXAMPLES section hereinbefore.

A Gal4-hFXR fusion construct reporter system was used as the primaryassay to characterize compound activity. A construct including 5 copiesof the Gal4 promoter response element upstream of a firefly luciferasereporter cDNA was stably expressed in HEK293 cells. This reporter cellline was maintained in Dulbecco's Modified Eagle's medium (DMEM; Gibco)supplemented with 1% penicillin-streptomycin (P/S) solution, 500 μg/mLZeocin and 10% charcoal/dextran-treated fetal bovine serum (cs-FBS) at37° C. in a humidified 5% CO₂ atmosphere. Another plasmid wasconstructed in which the human cytomegalovirus promoter in the pcDNA3.1vector directs the expression of the cDNA encoding a fusion proteincomprised of the DNA binding domain from the Gal4 transcription factorfused to the ligand binding domain from human FXR.

The day prior to transfection, the reporter cells in culture aredetached from the plate with trypsin and plated into a T75 flask at asufficient density to achieve approximately 90% confluence the nextmorning. The transfection reagents are prepared by separately diluting25 μg of the pcDNA3.1-Gal4-FXR plasmid into 1.87 mL of Opti-MEM(Thermo-Fisher), and 40 μL of Lipofectamine 2000 (Thermo-Fisher) into1.87 mL of Opti-MEM, and then adding the diluted DNA solution into thediluted Lipofectamine 2000 solution and incubating at room temperaturefor 15-20 minutes. The mixture is further diluted with 10 mL of asolution comprised of DMEM, 10% cs-FBS, and 1% P/S immediately prior totransferring to the cells. The maintenance culture media is aspiratedfrom the cells and the final transfection mixture is added before thecells are incubated overnight at 37° C. in a humidified 5% CO₂atmosphere. This protocol can be scaled up, and the transientlytransfected cells can be cryopreserved in an assay-ready format.

For compound testing, 100 nL of the compounds (serial dilutions in DMSO)are dispensed with an Echo acoustic dispenser (Labcyte) into the wellsof a Corning/Costar clear bottom 384-well white plate. The transfectedcells are harvested, counted, and diluted such that 10-25,000 cells in25 μL are plated into each well of the 384-well compound assay plate.The compound-treated cells are incubated overnight at 37° C. in ahumidified 5% CO₂ atmosphere. The next morning 25 μL of Steady-Glo(Promega) are added to each well of the plate, the mixture is incubatedfor 15 min. with shaking, and luminescence is measured on an Envision(Perkin Elmer) plate reader. Background counts from cells treated withDMSO alone are subtracted from all raw counts, and the corrected valuesare converted to a percentage of the control response attained with 8 μMGW-4064. These data are fit to a 4-parameter log agonist-responseequation to calculate an EC₅₀ value.

In Vivo Testing Example: Acute Mouse PK/PD

Male, C57BL6/NTac mice, weighing 25-28 g, are purchased from TaconicLabs (Hudson, N.Y.) and maintained on Teklad Global 18% Protein RodentDiet (Harlan Laboratories). After 1 week acclimation, mice are sortedinto groups based upon body weight. Mice are administered a single oraldose of vehicle or experimental compound. Systemic compound exposure isevaluated in plasma derived from blood collected via the submandibularvein at 1 hour post-dose, and at study termination (6 h). At studytermination, the animals are euthanized and rapidly dissected. Themedial lobe of the liver is divided, with one half being homogenized andanalyzed for compound exposure, and the other half saved in RNAlater(Thermo-Fisher Scientific). The ileum is also dissected and preserved inRNAlater. Tissue samples in RNAlater are homogenized with MPBiomedicals' beads. RNA is extracted using the MagMax-96 Total RNAIsolation kit (Thermo-Fisher Scientific) according to the manufacturer'sprotocol. RNA Concentration is determined with the Nano-Drop 8000Spectrophotometer (Thermo Fisher). Reverse transcription is done withInvitrogen's SuperScript® VILO cDNA Synthesis Kit according to themanufacturer's protocol. Real time PCR is done with Applied Biosystems'Taqman PCR master mixture according to the manufacturer's protocol. Allprimers are purchased from Thermo-Fisher Scientific. Mouse genesanalyzed include Nr0b2 (which encodes the small heterodimer partner,SHP), Abcbl 1 (which encodes the bile salt excretion pump, BSEP),Cyp7a1, & Cyp8b1 in liver, and Fgf15, Fabp6 (which encodes ileal bileacid binding protein, I-BABP), Slc51a (which encodes organic solutetransporter alpha subunit, OSTA), and Slc51 b (which encodes organicsolute transporter beta subunit, OSTB) in the ileum. The statisticalsignificant changes in FGF15 gene expression are expressed as foldincrease and CYP_(7A1) expression as a percent reduction relative tovehicle control.

TABLE A Mouse PD Cyp7a1 Fgf15 Example Dose (fold change@ 6 h (foldchange@ 6 h # (mg/kg) relative to Vehicle) relative to Vehicle) 27 300.10 2.8 101 3 0.06 21

Other features of the invention should become apparent in the course ofthe above descriptions of exemplary embodiments that are given forillustration of the invention and are not intended to be limitingthereof. The present invention may be embodied in other specific formswithout departing from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of preferred aspects of theinvention noted herein. It is understood that any and all embodiments ofthe present invention may be taken in conjunction with any otherembodiment or embodiments to describe additional embodiments. It is alsounderstood that each individual element of the embodiments is its ownindependent embodiment. Furthermore, any element of an embodiment ismeant to be combined with any and all other elements from any embodimentto describe an additional embodiment.

What is claimed is:
 1. A compound of Formula (I):

or a stereoisomer, a tautomer, or a pharmaceutically acceptable saltthereof; wherein: X¹ and X⁴ are each independently C or N; X² and X³ areeach independently CR⁵, N, NR⁶, O, or S; Y is CR⁷, or N; the dashedstraight line is an optional covalent bond; m and n are eachindependently an integer of 0, 1, or 2; provided that when m and n areboth 0, then the optional covalent bond of the dashed line is absent; fis an integer of 0, 1, 2, or 3; Z is 6- to 10-membered aryl, 5- to10-membered heteroaryl, 3- to 10-membered carbocyclyl, or 4- to10-membered heterocyclyl, wherein the aryl, heteroaryl, carbocyclyl, andheterocyclyl are independently substituted with 0 to 5 R⁸; L¹ is acovalent bond, O, S, NR″, S(O)₂, C₁₋₃ alkylene, C₁₋₃ heteroalkylene,C₂₋₄ alkenylene, C₂₋₄ alkynylene, aryl, or a 5- to 6-membered heteroarylcontaining 1 to 4 heteroatoms independently selected from N, O, and S;wherein the alkylene, heteroalkylene, aryl, and heteroaryl are eachindependently substituted with 0 to 3 R¹¹; L² is a covalent bond, O, S,NR¹⁸, C₁₋₃ alkylene, or C₁₋₃ heteroalkylene, wherein the alkylene andheteroalkylene are independently substituted with 0 to 3 R¹⁶; R^(X) is-L³-R^(Z); L³ is a covalent bond, a C₁₋₃ alkylene, or —C(O)NR¹²—CH₂—,wherein the C₁₋₃ alkylene is substituted with 0 to 3 R¹⁵; R^(Z) is —CN,—C(O)OR¹³, —C(O)NR^(14a)R^(14b),

R^(e) is C₁₋₆ alkyl, C₃₋₆ cycloalkyl, haloalkyl, hydroxyalkyl,aminoalkyl, alkoxyalkyl, or haloalkoxyalkyl; each R^(Y) is independentlyhydrogen, halo, cyano, hydroxyl, amino, C₁₋₆ alkyl, alkylamino,haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl,alkoxy, or haloalkoxy; or alternatively two R^(Y), together with thecarbon atoms to which they are attached, form a bridge moiety; and withthe proviso that when Y is N and R^(Y) is attached to a carbon atomadjacent to Y, then R^(Y) is not halo, cyano, hydroxyl, amino, alkoxy,or haloalkoxy; R¹ is C₁₋₆ alkyl, C₃₋₅ cycloalkyl, or C₄₋₆ heterocyclyl,wherein the alkyl and cycloalkyl are substituted with 0 to 3 R⁹; R² is6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-memberedcarbocyclyl, or 4- to 10-membered heterocyclyl, wherein the aryl,heteroaryl, carbocyclyl, and heterocyclyl are independently substitutedwith 0 to 5 R¹⁰; R³ and R⁴ are each independently hydrogen, C₁₋₆ alkyl,haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, or haloalkoxyalkyl; R⁵and R⁷ are each independently hydrogen, halo, cyano, hydroxyl, amino,C₁₋₆ alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl,alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy; R⁶, R¹⁷ and R¹⁸ areeach independently is hydrogen, C₁₋₆ alkyl, haloalkyl, hydroxyalkyl,aminoalkyl, alkoxyalkyl, or haloalkoxyalkyl; R⁸ and R¹⁰ are eachindependently halo, cyano, hydroxyl, amino, oxo, —OR^(a), —SR^(a), ═S,—NR^(c)R^(c), ═NH, ═N—OH, ═NR^(a), ═N—OR^(a), —NO₂, —S(O)₂R^(a),—S(O)₂NHR^(b), —S(O)₂NR^(c)R^(c), —S(O)₂OR^(b), —OS(O)₂R^(b),—OS(O)₂OR^(b), —P(O)(OR^(b))(OR^(b)), —C(O)R^(b), —C(NR^(b))R^(b),—C(O)OR^(b), —C(O)NR^(c)R^(c), —C(NR^(b))NR^(c)R^(c), —OC(O)R^(b),—NR^(b)C(O)R^(b), —OC(O)OR^(b), —NR^(b)C(O)OR^(b), —OC(O)NR^(c)R^(c),—NR^(b)C(O)NR^(c)R^(c), —NR^(b)C(NR^(b))R^(b),—NR^(b)C(NR^(b))NR^(c)R^(c), C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl,arylalkyl, heteroaryl, carbocyclyl, or heterocyclyl; wherein the alkyl,aryl, heteroaryl, carbocyclyl, and heterocyclyl, by themselves or aspart of another group, are each independently substituted with 0 to 5R^(d); R^(b) is each independently hydrogen or R^(a); R^(c) is eachindependently R^(b) or alternatively, the two R^(c) are taken togetherwith the nitrogen atom to which they are bonded form a 4, 5, 6 or7-membered heterocyclyl; R^(d) is each independently R^(a), alkoxy,haloalkoxy, alkylamino, cycloalkylamino, heterocyclylamino, haloalkyl,hydroxyalkyl, aminoalkyl, cycloalkoxy, heterocyclyloxy, haloalkoxy,alkoxyalkoxy, haloalkylamino, alkoxyalkylamino, haloalkoxyalkylamino,arylamino, aralkylamino, aryloxy, aralkyloxy, heteroaryloxy,heteroarylalkyloxy, alkylthio, halo, cyano, hydroxyl, amino, oxo,—OR^(a), —SR^(a), ═S, —NR^(c)R^(c), ═NH, ═N—OH, ═NR^(a), ═N—OR^(a),—NO₂, —S(O)₂R^(a), —S(O)₂NHR^(b), —S(O)₂NR^(c)R^(c), —S(O)₂OR^(b),—OS(O)₂R^(b), —OS(O)₂OR^(b), —P(O)(OR^(b))(OR^(b)), —C(O)R^(b),—C(NR^(b))R^(b), —C(O)OR^(b), —C(O)NR^(c)R^(c), —C(NR^(b))NR^(c)R^(c),—OC(O)R^(b), NR^(b)C(O)R^(b); —OC(O)OR^(b), —NR^(b)C(O)OR^(b),—NR^(b)C(O)NR^(c)R^(c), —NR^(b)C(NR^(b))R^(b), orNR^(b)C(NR^(b))NR^(c)R^(c); R⁹ is each independently halo, cyano,hydroxyl, amino, or C₁₋₆ alkyl; R¹¹ and R¹⁶ are each independently halo,oxo, cyano, hydroxyl, amino, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₄₋₆heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl,alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy; R¹² are eachindependently hydrogen or C₁₋₄ alkyl; R¹³ is hydrogen, C₁₋₁₀ alkyl, orglycosyl; R^(14a) and R^(14b) are each independently hydrogen, C₁₋₆alkyl, C₃₋₆ cycloalkyl, C₄₋₆ heterocyclyl, alkylamino, haloalkyl,hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, orhaloalkoxy; and R¹⁵ are each independently halo, oxo, cyano, hydroxyl,amino, alkyl, alkoxy, or alkylamino; or alternatively, two R¹⁵, takentogether with the atom(s) to which they are attached, form a carbocyclylor heterocyclyl moiety.
 2. The compound of claim 1, or a tautomer, or apharmaceutically acceptable salt thereof, which is represented byFormula (Ia):


3. The compound according to claim 1, or a stereoisomer, a tautomer, ora pharmaceutically acceptable salt thereof, wherein the

moiety is


4. The compound according to claim 1, or a stereoisomer, a tautomer, ora pharmaceutically acceptable salt thereof, wherein the

moiety is:


5. The compound according to claim 1, or a stereoisomer, a tautomer, ora pharmaceutically acceptable salt thereof, wherein: L¹ is a covalentbond, phenyl, thiazolyl, oxadiazolyl, thiadiazolyl, or pyridinyl; and Zis phenyl or 5- to 10-membered heteroaryl, wherein the phenyl andheteroaryl are independently substituted with 0 to 5 R⁸.
 6. The compoundaccording to claim 1, or a stereoisomer, a tautomer, or apharmaceutically acceptable salt thereof, wherein: L³ is a covalent bondor a C₁₋₂ alkylene, wherein the C₁₋₂ alkylene is substituted with 0 to 3R¹⁵; and R^(Z) is —CN, —C(O)OR¹³, —C(O)NR^(14a)R^(14b),


7. The compound according to claim 1, or a stereoisomer, a tautomer, ora pharmaceutically acceptable salt thereof, wherein: L² is a covalentbond: and R² is phenyl or 6-membered heteroaryl, wherein the phenyl andthe heteroaryl are substituted with 0 to 3 R¹⁰.
 8. The compoundaccording to claim 1, or a stereoisomer, a tautomer, or apharmaceutically acceptable salt thereof, wherein: the

moiety is

the

moiety is:

L¹ is a covalent bond, phenyl, thiazolyl, oxadiazolyl, thiadiazolyl, orpyridinyl; Z is 1,5-naphthyridinyl, benzo[d]imidazolyl,benzo[d]isothiazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, cinnolinyl,imidazo[3,4-a]pyridinyl, indazolyl, indolyl, isoquinolinyl, phenyl,pyrazinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[4,3-b]pyridinyl,pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolo[2,1-f]triazinyl,pyrrolo[2,3-b] pyridinyl, pyrrolo[2,3-d]pyrimidinyl,pyrrolo[3,2-b]pyridinyl, quinolinonyl, quinolinyl, quinoxalinyl,thiazolo[5,4-b]pyridinyl, or thiazolyl, each independently substitutedwith 0 to 2 R⁸; R^(X) is —CN, —C(O)OH, —CH₂C(O)OH, —C(O)NH₂,—C(O)NHS(O)₂CH₃,

R¹ is cyclopropyl; R² is phenyl or pyridinyl, each independentlysubstituted with 1 to 2 R¹⁰; R³ is hydrogen; R⁴ is hydrogen or —CH₃; R⁸is each independently F, Cl, —CH₃, —CH₂CH₃, —CH₂OCH₃, —CF₃, —OCH₃,—OCD₃, —OCH₂CH₃, —CH(CH₃)₂, —OCH₂CH₂OCH₃, —OCHF₂, —OCH₂CHF₂,—CH₂(cyclopropyl), —O(cyclopropyl), —O(cyclobutyl),—O(difluorocyclobutyl), —O(fluorocyclobutyl), —O(oxetanyl),—O(tetrahydrofuranyl), or —OCH₂(methoxyphenyl); L² is a covalent bond;and R¹⁰ is each independently Cl, —CF₃, or —OCF₃.
 9. The compound ofclaim 1 or a salt thereof, wherein said compound is:(E)-6-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)nicotinic acid (1);(E)-6-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)-1-methyl-1H-indole-3-carboxylicacid (2);(Z)-6-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)nicotinic acid (3);(E)-2-(4-(1-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)prop-1-en-2-yl)piperidin-1-yl)-4-fluorobenzo[d]thiazole-6-carboxylicacid (4);(E)-6-(4-(1-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)prop-1-en-2-yl)piperidin-1-yl)quinoline-2-carboxylicacid (5);(E)-2-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)-4-methylpiperidin-1-yl)-4-fluorobenzo[d]thiazole-6-carboxylicacid (6);(E)-6-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)-4-methylpiperidin-1-yl)quinoline-2-carboxylicacid (7);(E)-2-(6-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-4-fluorobenzo[d]thiazole-6-carboxylicacid (8);(E)-6-(6-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-2-carboxylicacid (9);(E)-2-(4-(2-(4-cyclopropyl-1-(2,6-dichlorophenyl)-1H-1,2,3-triazol-5-yl)vinyl)piperidin-1-yl)-4-fluorobenzo[d]thiazole-6-carboxylicacid (10);(E)-6-(4-(2-(4-cyclopropyl-1-(2,6-dichlorophenyl)-1H-pyrazol-5-yl)vinyl)piperidin-1-yl)nicotinic acid (11);(E)-2-(4-(2-(1-cyclopropyl-4-(2,6-dichlorophenyl)-1H-pyrazol-5-yl)vinyl)piperidin-1-yl)-4-fluorobenzo[d]thiazole-6-carboxylicacid (12);(E)-6-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)picolinic acid (13);(E)-2-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)-4-fluorobenzo[d]thiazole-6-carboxylicacid (14);(Z)-2-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)-4-fluorobenzo[d]thiazole-6-carboxylicacid (15);(E)-6-(4-(2-(4-cyclopropyl-1-(2,6-dichlorophenyl)-1H-1,2,3-triazol-5-yl)vinyl)piperidin-1-yl)nicotinicacid (16);(Z)-2-(3-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)-8-azabicyclo[3.2.1]octan-8-yl)-4-fluorobenzo[d]thiazole-6-carboxylicacid (17);(E)-6-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)pyridazine-3-carboxylic acid (18);(E)-2-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylicacid (19);(E)-6-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid (20);(E)-6-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)-5-fluoronicotinicacid (21);(E)-2-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)benzo[d]thiazole-6-carboxylic acid (22);(E)-2-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)benzo[d]oxazole-5-carboxylic acid (23);(E)-5-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)pyrazine-2-carboxylic acid (24);(E)-2-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)pyrimidine-5-carboxylic acid (25);(E)-6-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)quinoline-2-carboxylic acid (26);(E)-5-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)pyrimidine-2-carboxylic acid (27);(E)-2-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)-1-methyl-1H-benzo[d]imidazole-5-carboxylicacid (28);(E)-2-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxylic acid (29);(E)-5-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)picolinic acid (30);(E)-3-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)-1-methyl-1H-pyrazolo[4,3-b]pyridine-6-carboxylicacid (31);(E)-2-(4-(2-(4-cyclopropyl-1-(2,6-dichlorophenyl)-1H-pyrazol-5-yl)vinyl)piperidin-1-yl)-4-fluorobenzo[d]thiazole-6-carboxylicacid (32);(E)-2-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)quinoline-6-carboxylic acid (33);(E)-6-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)-4-methylpiperidin-1-yl)nicotinicacid (34);(E)-6-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)-1-methyl-1H-indole-2-carboxylicacid (35);(E)-2-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)isonicotinic acid (36);(E)-7-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)isoquinoline-3-carboxylic acid (37);(E)-6-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)-4-(trifluoromethyl)quinoline-2-carboxylicacid (38);(E)-6-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)-3-(trifluoromethyl)imidazo[1,5-a]pyridine-1-carboxylicacid (39);(E)-2-(2-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)pyridin-4-yl)acetic acid (40);(E)-6-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)-1-methyl-1H-indazole-3-carboxylicacid (41);(E)-6-(4-(2-(5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)nicotinic acid (42);(E)-2-(4-(2-(5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)-4-fluorobenzo[d]thiazole-6-carboxylicacid (43);(E)-6-(4-(2-(5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)-4-(trifluoromethyl)quinoline-2-carboxylicacid (44);(E)-6-(4-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)-4-(trifluoromethyl)quinoline-2-carboxylicacid (45);(E)-2-(6-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)benzo[d]thiazole-6-carboxylicacid (46);(E)-4-(6-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)benzoicacid (47);(E)-7-(6-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)isoquinoline-3-carboxylicacid (48);(E)-2-(4-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)-4-fluorobenzo[d]thiazole-6-carboxylicacid (49);(E)-4-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)benzonitrile (50);(E)-4-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)-2-fluorobenzoicacid (51);(E)-6-(6-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-4-(trifluoromethyl)quinoline-2-carboxylicacid (52);(E)-2-chloro-4-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)benzoicacid (53);(E)-4-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)benzoicacid (54);(E)-6-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)-2-(trifluoromethyl)nicotinicacid (55);(E)-4-(2-(1-(4-(1H-tetrazol-5-yl)phenyl)piperidin-4-yl)vinyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole(56);(E)-4-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)-2-(trifluoromethyl)benzoicacid (57);(E)-6-(4-(2-(4-cyclopropyl-1-(2,6-dichlorophenyl)-1H-1,2,3-triazol-5-yl)vinyl)piperidin-1-yl)-4-(trifluoromethyl)quinoline-2-carboxylicacid (58);(E)-1-(4-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)phenyl)cyclopropane-1-carboxylic acid (59);(E)-6-(4-(2-(4-cyclopropyl-1-(2,6-dichlorophenyl)-1H-1,2,3-triazol-5-yl)vinyl)piperidin-1-yl)quinoline-2-carboxylicacid (60);(E)-4-(2-(3-(4-(2H-tetrazol-5-yl)phenyl)-3-azabicyclo[3.1.0]hexan-6-yl)vinyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole(61);(E)-4-(2-(1-(4-(2H-tetrazol-5-yl)phenyl)piperidin-4-yl)vinyl)-5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole(62);(E)-4-(2-(1-(3-(2H-tetrazol-5-yl)phenyl)piperidin-4-yl)vinyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole(63);(E)-4-(2-(1-(5-(2H-tetrazol-5-yl)pyridin-2-yl)piperidin-4-yl)vinyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole(64);(E)-4-(2-(3-(2-(1H-tetrazol-5-yl)quinolin-6-yl)-3-azabicyclo[3.1.0]hexan-6-yl)vinyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole(65);(E)-7-(6-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)cinnoline-3-carboxylicacid (66);(E)-7-(4-(2-(5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)cinnoline-3-carboxylicacid (67);(E)-6-(6-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1-methyl-1H-indole-3-carboxylicacid (68);(E)-7-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)quinoline-3-carboxylic acid (69);(E)-4-(6-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)benzamide(70);(E)-4-(6-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-N-(methylsulfonyl)benzamide(71);(E)-6-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-4-(trifluoromethyl)quinoline-2-carboxylicacid (72);(E)-7-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)isoquinoline-3-carboxylicacid (73);(E)-6-(6-(2-(5-cyclopropyl-3-(2-fluoro-6-(trifluoromethoxy)phenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-4-(trifluoromethyl)quinoline-2-carboxylicacid (74);(E)-6-(6-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-4-(trifluoromethyl)quinoline-2-carboxylicacid (75);(E)-7-(6-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)isoquinoline-3-carboxylicacid (76);(E)-2-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-4-fluorobenzo[d]thiazole-6-carboxylicacid (77);(E)-2-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)benzo[d]thiazole-6-carboxylicacid (78);(E)-2-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-6-carboxylicacid (79);(E)-6-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-4-methoxyquinoline-2-carboxylicacid (80);(E)-2-(6-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)thiazolo[5,4-b]pyridine-5-carboxylicacid (81);(E)-6-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-2-carboxylicacid (82);(E)-6-(4-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)piperidin-1-yl)-4-(trifluoromethyl)quinoline-2-carboxylicacid (83);(E)-6-(4-(2-(3-(3-chloropyridin-4-yl)-5-cyclopropylisoxazol-4-yl)vinyl)piperidin-1-yl)-4-(trifluoromethyl)quinoline-2-carboxylicacid (84);(E)-2-(4-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)piperidin-1-yl)thiazolo[5,4-b]pyridine-5-carboxylic acid (85);(E)-2-(6-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)thiazole-5-carboxylicacid (86);(E)-2-(4-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)thiazolo[5,4-b]pyridine-5-carboxylic acid (87);(E)-6-(4-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)piperidin-1-yl)-4-methoxyquinoline-2-carboxylicacid (88);(E)-6-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1-methyl-1H-indole-3-carboxylicacid (89);(E)-7-(4-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)isoquinoline-3-carboxylicacid (90);(E)-6-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-4-(difluoromethoxy)quinoline-2-carboxylicacid (91);(E)-6-(4-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)piperidin-1-yl)-4-(difluoromethoxy)quinoline-2-carboxylicacid (92);(E)-2-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)benzo[d]thiazole-7-carboxylicacid (93);(E)-6-(4-(2-(5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)-4-methylquinoline-2-carbonitrile(94);(E)-6-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)benzo[d]isothiazole-3-carboxylicacid (95);(E)-4-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)benzoicacid (96);(E)-6-(4-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)pyridin-3-yl)isoxazol-4-yl)vinyl)piperidin-1-yl)-4-(trifluoromethyl)quinoline-2-carboxylicacid (97);(E)-6-(4-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)pyridin-3-yl)isoxazol-4-yl)vinyl)piperidin-1-yl)-4-(difluoromethoxy)quinoline-2-carboxylicacid (98);(E)-6-(4-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)-4-(difluoromethoxy)quinoline-2-carboxylicacid (99);(E)-6-(4-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)-4-methoxyquinoline-2-carboxylicacid (100);(E)-7-(4-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)piperidin-1-yl)isoquinoline-3-carboxylic acid (101);(E)-6-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)nicotinicacid (102);(E)-7-(4-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)pyridin-3-yl)isoxazol-4-yl)vinyl)piperidin-1-yl)isoquinoline-3-carboxylicacid (103);(E)-6-(4-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)piperidin-1-yl)isoquinoline-1-carboxylic acid (104)(E)-6-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)isoquinoline-1-carboxylicacid (105);(E)-6-(4-(2-(5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)isoquinoline-1-carboxylic acid (106);(E)-6-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)benzo[d]thiazole-2-carboxylicacid (107);(E)-6-(4-(2-(5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)-4-isopropoxyquinoline-2-carboxylicacid (108);(E)-6-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-4-isopropoxyquinoline-2-carboxylicacid (109);(E)-6-(4-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)pyridin-3-yl)isoxazol-4-yl)vinyl)piperidin-1-yl)-4-isopropoxyquinoline-2-carboxylicacid (110);(E)-6-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-4-methylquinoline-2-carboxylicacid (111);(E)-2-(4-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)piperidin-1-yl)-7-methylthiazolo[5,4-b]pyridine-5-carboxylicacid (112);(E)-6-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-4-(2-methoxyethoxy)quinoline-2-carboxylicacid (113);(E)-2-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-4-methoxybenzo[d]thiazole-6-carboxylicacid (114);(E)-7-(4-(2-(5-cyclopropyl-3-(3-(trifluoromethyl)pyridin-2-yl)isoxazol-4-yl)vinyl)piperidin-1-yl)isoquinoline-3-carboxylicacid (115);(E)-4-(3-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,2,4-oxadiazol-5-yl)benzoicacid (116);(E)-3-(3-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,2,4-oxadiazol-5-yl)benzoicacid (117);(E)-6-(4-(2-(5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (118);(E)-7-(4-(2-(5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)vinyl)piperidin-1-yl)-1-methylisoquinoline-3-carboxylicacid (119);(E)-6-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-4-((tetrahydrofuran-3-yl)oxy)quinoline-2-carboxylicacid (120);(E)-8-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-5-carboxylicacid (121);(E)-7-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1-methoxyisoquinoline-3-carboxylicacid (122);(E)-3-(3-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,2,4-oxadiazol-5-yl)-5-(trifluoromethyl)benzoicacid (123);(E)-2-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-7-methoxythiazolo[5,4-b]pyridine-5-carboxylicacid (124);(E)-6-(4-(2-(5-cyclopropyl-3-(3-(trifluoromethyl)pyridin-2-yl)isoxazol-4-yl)vinyl)piperidin-1-yl)-4-methoxyquinoline-2-carboxylicacid (125);(E)-6-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-4-(oxetan-3-yloxy)quinoline-2-carboxylicacid (126);6-(6-((E)-2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-4-(((R)-tetrahydrofuran-3-yl)oxy)quinoline-2-carboxylicacid (127);6-(6-((E)-2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-4-(((S)-tetrahydrofuran-3-yl)oxy)quinoline-2-carboxylicacid (128);(E)-6-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-4-((4-methoxybenzyl)oxy)quinoline-2-carboxylicacid (129);(E)-4-cyclobutoxy-6-(6-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-2-carboxylicacid (130);(E)-3-(3-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,2,4-oxadiazol-5-yl)-5-methoxybenzoicacid (131);(E)-6-(6-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-4-methoxyquinoline-2-carboxylicacid (132);(E)-3-(5-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,2,4-oxadiazol-3-yl)benzoicacid (133);(E)-6-(6-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-4-(oxetan-3-yloxy)quinoline-2-carboxylicacid (134);(E)-7-(6-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1-methoxyisoquinoline-3-carboxylicacid (135);(E)-4-cyclobutoxy-6-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-2-carboxylicacid (136);(E)-3-(3-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,2,4-oxadiazol-5-yl)-5-(oxetan-3-yloxy)benzoicacid (137);(E)-7-(6-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoxaline-2-carboxylicacid (138);(E)-2-(6-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-7-methoxythiazolo[5,4-b]pyridine-5-carboxylicacid (139);(E)-6-(6-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoxaline-2-carboxylicacid (140);(E)-6-(6-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)pyridin-3-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-4-methoxyquinoline-2-carboxylicacid (141);(E)-4-cyclobutoxy-6-(6-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)pyridin-3-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-2-carboxylic acid (142);(E)-6-(6-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)pyridin-3-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-4-(oxetan-3-yloxy)quinoline-2-carboxylicacid (143);(E)-6-(6-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)nicotinicacid (144);(S,E)-6-(3-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)pyrrolidin-1-yl)-4-(trifluoromethyl)quinoline-2-carboxylicacid (145);(R,E)-6-(3-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)pyrrolidin-1-yl)-4-(trifluoromethyl)quinoline-2-carboxylicacid (146);(S,E)-4-cyclobutoxy-6-(3-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)pyrrolidin-1-yl)quinoline-2-carboxylic acid (147);(R,E)-4-cyclobutoxy-6-(3-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)pyrrolidin-1-yl)quinoline-2-carboxylic acid (148);(E)-6-(3-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)azetidin-1-yl)-4-isopropoxyquinoline-2-carboxylicacid (149);(E)-4-cyclobutoxy-6-(3-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)azetidin-1-yl)quinoline-2-carboxylic acid (150);(E)-6-(3-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)azetidin-1-yl)-4-(oxetan-3-yloxy)quinoline-2-carboxylicacid (151);(E)-6-(3-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)azetidin-1-yl)-4-(3,3-difluorocyclobutoxy)quinoline-2-carboxylicacid (152);(E)-2-(3-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)azetidin-1-yl)-7-methoxythiazolo[5,4-b]pyridine-5-carboxylicacid (153);(E)-6-(3-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)azetidin-1-yl)-4-methoxyquinoline-2-carboxylicacid (154);(E)-3-(3-(6-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)pyridin-3-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,2,4-oxadiazol-5-yl)-5-methoxybenzoicacid (155);(E)-6-(6-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)pyridin-3-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-4-ethoxyquinoline-2-carboxylicacid (156);6-(6-((E)-2-(5-cyclopropyl-3-(2-(trifluoromethyl)pyridin-3-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-4-(((R)-tetrahydrofuran-3-yl)oxy)quinoline-2-carboxylicacid (157);(E)-5-(6-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-ethoxypicolinamide(158);(E)-4-cyclobutoxy-6-(3-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)azetidin-1-yl)quinoline-2-carboxylic acid (159);(E)-6-(3-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)azetidin-1-yl)-4-(oxetan-3-yloxy)quinoline-2-carboxylicacid (160);(E)-6-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoxaline-2-carboxylicacid (161);(E)-6-(3-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)azetidin-1-yl)-4-(trifluoromethyl)quinoline-2-carboxylicacid (162);(E)-5-(6-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-3-ethoxypicolinicacid (163);(E)-4-(3-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,2,4-oxadiazol-5-yl)-6-methoxypicolinicacid (164);(E)-3-(3-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,2,4-oxadiazol-5-yl)-5-methoxybenzoicacid (165);(E)-6-(3-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)azetidin-1-yl)-4-methoxyquinoline-2-carboxylicacid (166);(E)-6-(3-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)azetidin-1-yl)quinoxaline-2-carboxylic acid (167);(E)-3-(3-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,2,4-oxadiazol-5-yl)-2-methoxybenzoicacid (168);(E)-6-(3-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)pyridin-3-yl)isoxazol-4-yl)vinyl)azetidin-1-yl)-4-methoxyquinoline-2-carboxylicacid (169);(E)-4-cyclobutoxy-6-(3-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)pyridin-3-yl)isoxazol-4-yl)vinyl)azetidin-1-yl)quinoline-2-carboxylic acid (170);(E)-6-(3-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)pyridin-3-yl)isoxazol-4-yl)vinyl)azetidin-1-yl)-4-(methoxymethyl)quinoline-2-carboxylicacid (171);(E)-6-(3-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)azetidin-1-yl)-4-(methoxy-d3)quinoline-2-carboxylicacid (172);(E)-6-(3-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)azetidin-1-yl)-4-methoxy-1,5-naphthyridine-2-carboxylicacid (173);(E)-6-(3-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)pyridin-3-yl)isoxazol-4-yl)vinyl)azetidin-1-yl)-4-(oxetan-3-yloxy)quinoline-2-carboxylicacid (174);(E)-6-(6-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)pyridin-3-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-4-methoxy-1,5-naphthyridine-2-carboxylicacid (175);(E)-5-(3-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,2,4-oxadiazol-5-yl)-2-methoxybenzoicacid (176);(E)-4-cyclopropoxy-6-(3-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)pyridin-3-yl)isoxazol-4-yl)vinyl)azetidin-1-yl)quinoline-2-carboxylicacid (178);(E)-7-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylicacid (180);(E)-7-(3-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)azetidin-1-yl)-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylicacid (181);(E)-6-(3-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)azetidin-1-yl)-4-(2,2-difluoroethoxy)quinoline-2-carboxylicacid (182);(E)-4-cyclopropoxy-6-(6-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-2-carboxamide (183);(E)-4-cyclopropoxy-6-(6-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)quinoline-2-carboxylic acid (184);6-(6-((E)-2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-4-((1S,3S)-3-fluorocyclobutoxy)quinoline-2-carboxylicacid (185);(E)-6-(3-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)azetidin-1-yl)-4-(methoxymethyl)quinoline-2-carboxylicacid (186);6-(3-((E)-2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)azetidin-1-yl)-4-((1S,3S)-3-fluorocyclobutoxy)quinoline-2-carboxylicacid (187);(R,E)-6-(3-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)pyridin-3-yl)isoxazol-4-yl)vinyl)azetidin-1-yl)-4-((tetrahydrofuran-3-yl)oxy)quinoline-2-carboxylicacid (188);(S,E)-6-(3-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)pyridin-3-yl)isoxazol-4-yl)vinyl)azetidin-1-yl)-4-((tetrahydrofuran-3-yl)oxy)quinoline-2-carboxylicacid (189);(E)-7-(6-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylicacid (190);(E)-6-(6-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-4-(2,2-difluoroethoxy)quinoline-2-carboxylicacid (191);(E)-7-(6-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1-ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylicacid (192);(S,E)-6-(3-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)azetidin-1-yl)-4-((tetrahydrofuran-3-yl)oxy)quinoline-2-carboxylicacid (193);6-(3-((E)-2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)azetidin-1-yl)-4-((1R,3R)-3-fluorocyclobutoxy)quinoline-2-carboxylicacid (194);6-(3-((E)-2-(5-cyclopropyl-3-(2-(trifluoromethyl)pyridin-3-yl)isoxazol-4-yl)vinyl)azetidin-1-yl)-4-((1S,3S)-3-fluorocyclobutoxy)quinoline-2-carboxylicacid (195);(E)-4-cyclopropoxy-6-(3-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)azetidin-1-yl)quinoline-2-carboxylic acid (196);(E)-7-(3-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)azetidin-1-yl)-1-(cyclopropylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid (197);(E)-6-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-8-fluoro-4-methoxyquinoline-2-carboxylicacid (198);6-(6-((E)-2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-4-((1R,3R)-3-fluorocyclobutoxy)quinoline-2-carboxylicacid (199);(E)-6-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-4-(2,2-difluoroethoxy)quinoline-2-carboxylicacid (200);(E)-6-(3-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)azetidin-1-yl)-1-methyl-1H-indole-3-carboxylicacid (201);(E)-6-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-4-(methoxy-d3)quinoline-2-carboxylicacid (202);6-(6-((E)-2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-4-((1S,3S)-3-fluorocyclobutoxy)quinoline-2-carboxylicacid (203);6-(6-((E)-2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-4-((1R,3R)-3-fluorocyclobutoxy)quinoline-2-carboxylicacid (204);(E)-4′-(3-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)azetidin-1-yl)-[1,1′-biphenyl]-4-carboxylicacid (205);(E)-6-(3-(2-(5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)vinyl)azetidin-1-yl)-4-methoxyquinoline-2-carboxylicacid (206);(E)-4′-(3-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)azetidin-1-yl)-[1,1′-biphenyl]-3-carboxylicacid (207);(E)-3-(2-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)thiazol-4-yl)-5-methoxybenzoicacid (208);(E)-6-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylicacid (209);(E)-3-(3-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,2,4-thiadiazol-5-yl)-5-methoxybenzoicacid (210);(E)-6-(6-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylicacid (211);(E)-6-(6-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-(cyclopropylmethyl)-2H-indazole-3-carboxylicacid (212);(E)-6-(6-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1-(cyclopropylmethyl)-1H-indazole-3-carboxylicacid (213);(E)-3-(5-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,2,4-thiadiazol-3-yl)-5-methoxybenzoicacid (214);(E)-6-(3-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)azetidin-1-yl)-8-fluoro-4-methoxyquinoline-2-carboxylicacid (215);(E)-3-(2-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)thiazol-5-yl)-5-methoxybenzoicacid (216);(E)-4-cyclopropoxy-6-(3-(2-(3-(2-(trifluoromethoxy)phenyl)-5-(trifluoromethyl)isoxazol-4-yl)vinyl)azetidin-1-yl)quinoline-2-carboxylicacid (217);(E)-3-(5-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4-oxadiazol-2-yl)benzoicacid (218);(E)-4′-(3-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)azetidin-1-yl)-5-methoxy-[1,1′-biphenyl]-3-carboxylicacid (219);(E)-1-(4-(3-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)azetidin-1-yl)phenyl)-1H-pyrazole-4-carboxylic acid (220);(E)-3-(5-(3-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)azetidin-1-yl)pyridin-2-yl)-5-methoxybenzoic acid (221);(E)-3-(6-(3-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)azetidin-1-yl)pyridin-3-yl)-5-methoxybenzoic acid (222)(E)-3-(5-(6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)-3-azabicyclo[3.1.0]hexan-3-yl)-1,3,4-thiadiazol-2-yl)-5-methoxybenzoicacid (223);(E)-3-(6-(3-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)vinyl)azetidin-1-yl)pyridin-3-yl)-5-(trifluoromethyl)benzoic acid (224);(E)-3-(6-(3-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)azetidin-1-yl)pyridin-3-yl)-5-(trifluoromethyl)benzoic acid (225);(E)-3-(6-(3-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)azetidin-1-yl)pyridin-3-yl)-5-fluorobenzoic acid (226); or(E)-3-(5-(3-(2-(5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)vinyl)azetidin-1-yl)pyridin-2-yl)-5-(trifluoromethyl)benzoic acid (227).
 10. Apharmaceutical composition comprising a pharmaceutically acceptablecarrier and a compound according to claim 1, or a pharmaceuticallyacceptable salt thereof.
 11. The compound according to claim 1 or a saltthereof, wherein: the

moiety is

moiety is:

Z is cyclopropyl, phenyl, pyrazolyl, thiazolyl, pyridinyl, pyridazinyl,pyrazinyl, pyrimidinyl, indolyl, indazolyl, benzo[d]thiazolyl,pyrrolo[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl,pyrrolo[3,2-b]pyridinyl, benzo[d]oxazolyl, benzo[d]imidazolyl,pyrrolo[2,1-f]triazinyl, pyrazolo[4,3-b]pyridinyl,pyrrolo[2,1-f]triazinyl, pyrazolo[4,3-b]pyridinyl, thiazolo[5,4-b]pyridinyl, benzo[d]isothiazolyl, pyrazolo[1,5-a]pyridinyl, quinolinyl,isoquinolinyl, quinolinonyl, cinnolinyl, quinoxalinyl or1,5-naphthyridinyl, L¹ is a covalent bond, phenyl, thiazolyl,oxadiazolyl, or thiadiazolyl; L² is a covalent bond; L³ is a covalentbond or —CH₂—; R^(Z) is —CN, —C(O)NH₂, —C(O)NHS(O)₂CH₃, or

R¹ is —CF₃ or cyclopropyl; R² is phenyl, pyridinyl, independentlysubstituted with 0 to 5 R¹⁰; R³ is hydrogen; R⁴ is hydrogen or —CH₃;each R⁸ is independently F, Cl, —CH₃, or —CF₃; and each R¹⁰ isindependently Cl, —CH₃, —CH₂CH₃, —CH₂(cyclopropyl), —CF₃, —CH₂OCH₃,—OCH₃, —OCD₃, —OCH₂CH₃, —OCH(CH₃)₂, —O(CH(CH₃)₂), —OCHF₂, —OCF₃,—OCH₂CHF₂, —OCH₂CH₂OCH₃, —O(cyclopropyl), —O(cyclobutyl),—O(fluorocyclobutyl), —O(difluorocyclobutyl), —O(oxetanyl),—O(tetrahydrofuranyl), or —OCH₂(methoxphenyl).